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Evidence for the substantia nigra pars compacta as an essential component of a memory system independent of the hippocampal memory system
Abstract
The aim of the present study was to test if the nigrostriatal pathway is an essential component for a water maze cued task learning and if it works independently of the hippocampal memory system. This hypothesis was tested using an animal model of Parkinson's disease in which male Wistar rats were lesioned in the substantia nigra pars compacta (SNc) by the intranigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), thus causing a partial depletion of striatal dopamine. SNc-lesioned and sham-operated animals were implanted bilaterally with guide cannulae above the dorsal hippocampus in order to be tested after the administration of 0.4 microl 2% lidocaine or saline into this structure. The animals were tested in a spatial or in a cued version of the water maze, memory tasks previously reported to model hippocampal-dependent spatial/relational and striatal-dependent S-R learning, respectively. Hippocampal inactivation, but not SNc lesion, impaired learning and memory in the spatial version of the water maze. An opposite situation was observed with the cued version. No significant interaction was observed between the SNc lesion and hippocampal inactivation conditions affecting scores in the spatial or in the cued version of the water maze. These results suggest that the nigrostriatal pathway is an essential part of the memory system that processes S-R learning and that it works independently of the hippocampal memory system that processes spatial/relational memories.
... Therefore, it is of great interest to look for neuroprotective compounds for the treatment of Parkinson's disease. 6-Hydroxydopamine (6-OHDA) and 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cause large or partial loss of dopaminergic cells, respectively, in the SNc of rats. Their effects have been studied as models of the advanced or the early phase of Parkinson's disease (4-7). ...
... 6-OHDA induces nigral dopaminergic lesion mainly by generating reactive oxygen species as a result of its oxidation. This can occur spontaneously or be induced by monoamine oxidase or iron (1,6). MPTP is converted into 1-methyl-4phenyl-peridinium (MPP + ) by glial monoamine oxidase B. MPP + accumulates in SNc dopaminergic cells and acts mainly by inhibiting mitochondrial complex I, leading to a decrease in cellular ATP levels and cell death (8). ...
... Three weeks after surgery, the animals were submitted to a working memory version of the Morris water maze task (6). The animals were submitted to 4 consecutive trials per day over 5 training days. ...
There is a great concern in the literature for the development of neuroprotectant drugs to treat Parkinson's disease. Since anesthetic drugs have hyperpolarizing properties, they can possibly act as neuroprotectants. In the present study, we have investigated the neuroprotective effect of a mixture of ketamine (85 mg/kg) and xylazine (3 mg/kg) (K/X) on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA) rat models of Parkinson's disease. The bilateral infusion of MPTP (100 µg/side) or 6-OHDA (10 µg/side) into the substantia nigra pars compacta of adult male Wistar rats under thiopental anesthesia caused a modest (~67%) or severe (~91%) loss of tyrosine hydroxylase-immunostained cells, respectively. On the other hand, an apparent neuroprotective effect was observed when the rats were anesthetized with K/X, infused 5 min before surgery. This treatment caused loss of only 33% of the nigral tyrosine hydroxylase-immunostained cells due to the MPTP infusion and 51% due to the 6-OHDA infusion. This neuroprotective effect of K/X was also suggested by a less severe reduction of striatal dopamine levels in animals treated with these neurotoxins. In the working memory version of the Morris water maze task, both MPTP- and 6-OHDA-lesioned animals spent nearly 10 s longer to find the hidden platform in the groups where the neurotoxins were infused under thiopental anesthesia, compared to control animals. This amnestic effect was not observed in rats infused with the neurotoxins under K/X anesthesia. These results suggest that drugs with a pharmacological profile similar to that of K/X may be useful to delay the progression of Parkinson's disease.
... Since DAergic neurons are particularly vulnerable to inflammatory cytokines [59], cytokines have been implicated in the neuronal and cognitive impairments in PD [44]. 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that selectively damages DAergic cells in the substantia nigra pars compacta (SNc), is widely used to induce models of PD in rodents and primates [18,25,26,60,84]. MPTP causes not only motor dysfunction and DAergic degeneration in the brain [13,25], but also neuroinflammation [45], for example, inducing microglial activation [92,96] and increasing levels of inflammatory cytokines, including IL-2, in animals [98] and humans [62]. ...
... Impairment of executive and visuospatial functions is observed not only in patients with PDD [16,22], but also in people exposed to MPTP [91]. In addition, cognitive impairment has been observed in MPTP-lesioned rats in the two-way active avoidance task [26] or Morris water maze test [18,25,60], as well as in monkeys in object recognition tasks [84]. Our previous study demonstrated that the behavioral deficits observed in MPTPlesioned rats may be similar to the behavioral symptoms seen in PDD patients [92,98]. ...
... Furthermore, DCS improves memory in aging rats [6,7], overcomes brain damage-induced impairments in LTP and object recognition in rats [103], and enhances episodic-like memory in MPTP-lesioned rats [96]. MPTP-induced glutamatergic dysfunction has been suggested to be involved in cognitive dysfunction after MPTP lesioning [18,25,26,60,84]. DCS may ameliorate neuronal and behavioral deficits by regulating the activity of glutamatergic NMDA receptors. ...
... The selective involvement of these different brain structures in the two versions of the MWM is clear from the results of several studies. A selective lesion in the SNpc ( Miyoshi et al. 2002;Da Cunha et al. 2003;Tadaiesky et al. 2008), which mainly projects to the striatum, or the systemic MPTP treatment ( Pothakos et al. 2009) selectively impaired the learning process as well as the memory test performance of rodents in the cued, but not in the spatial, version of MWM. Those behavioral observations were accompanied by a reduction of dopamine levels in the striatum and prefrontal cortex, but not in the hippocampus ( Miyoshi et al. 2002;Da Cunha et al. 2003). ...
... A selective lesion in the SNpc ( Miyoshi et al. 2002;Da Cunha et al. 2003;Tadaiesky et al. 2008), which mainly projects to the striatum, or the systemic MPTP treatment ( Pothakos et al. 2009) selectively impaired the learning process as well as the memory test performance of rodents in the cued, but not in the spatial, version of MWM. Those behavioral observations were accompanied by a reduction of dopamine levels in the striatum and prefrontal cortex, but not in the hippocampus ( Miyoshi et al. 2002;Da Cunha et al. 2003). Conversely, the bilateral injection of 6OHDA into the dorsal and ventral subiculum and adjacent CA1 hippocampus area ( Gasbarri et al. 1996) selectively affected the test performance in the spatial, but not in the cued, version of MWM. ...
... Conversely, the bilateral injection of 6OHDA into the dorsal and ventral subiculum and adjacent CA1 hippocampus area ( Gasbarri et al. 1996) selectively affected the test performance in the spatial, but not in the cued, version of MWM. Moreover, in the aforementioned study conducted by Da Cunha and colleagues, the otherwise normal performance in the spatial version of the test could be worsened by hippocampal injection of lidocaine (Da Cunha et al. 2003). In addition to these data obtained with pharmacological models of PD, transgenic mice expressing a-synuclein aggregates in the temporal cortex and the hippocampus ( Freichel et al. 2007;Masliah et al. 2011) also showed deficits in the spatial protocol. ...
Parkinson's disease (PD) has been, until recently, mainly defined by the presence of characteristic motor symptoms, such as rigidity, tremor, bradykinesia/akinesia, and postural instability. Accordingly, pharmacological and surgical treatments have so far addressed these motor disturbances, leaving nonmotor, cognitive deficits an unmet clinical condition. At the preclinical level, the large majority of studies aiming at defining mechanisms and testing novel therapies have similarly focused on the motor aspects of PD. Unfortunately, deterioration of the executive functions, such as attention, recognition, working memory, and problem solving, often appear in an early, premotor phase of the disease and progressively increase in intensity, negatively affecting the quality of life of ∼50%-60% of PD patients. At present, the cellular mechanisms underlying cognitive impairments in PD patients are largely unknown and an adequate treatment is still missing. The preclinical research has recently developed new animal models that may open new perspectives for a more integrated approach to the treatment of both motor and cognitive symptoms of the disease. This review will provide an overview on the cognitive symptoms occurring in early PD patients and then focus on the rodent and nonhuman primate models so far available for the study of discriminative and spatial memory attention and learning abilities related to this pathological condition.
... 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin selectively damaging DAergic cells in the substantia nigra pars compacta (SNc), is widely used to induce animal models of PD in rodents and primates (Da Cunha et al., 2003;Ferro et al., 2005;Gevaerd et al., 2001;Miyoshi et al., 2002;Schneider et al., 2000). Microinjection of MPTP into the SNc results in a pathophysiology similar to that seen in PD and causes not only DAergic degeneration, neuroinflammation (Barcia et al., 2004;Wada et al., 2006), and motor dysfunction (Capitelli et al., 2008;Ferro et al., 2005), but also hyperactivation in the glutamatergic system (Robinson et al., 2003). ...
... Microinjection of MPTP into the SNc results in a pathophysiology similar to that seen in PD and causes not only DAergic degeneration, neuroinflammation (Barcia et al., 2004;Wada et al., 2006), and motor dysfunction (Capitelli et al., 2008;Ferro et al., 2005), but also hyperactivation in the glutamatergic system (Robinson et al., 2003). In addition, cognitive impairment has been observed in MPTP-lesioned rats, which show disturbances of learning in the two-way active avoidance test and the Morris water maze test (Da Cunha et al., 2003;Ferro et al., 2005;Gevaerd et al., 2001). Moreover, MPTP-lesioned monkeys show deficits in object recognition tasks (Schneider et al., 2000). ...
... The striatum's function is intricately related to the nigral dopaminergic input via the nigrostriatal pathway (Nicola et al. 2000). Dopaminergic projections from the ventral tegmental area (lower part of the "midbrain" or mesencephalon) to the prefrontal cortex (Da Cunha et al. 2003). There are four different pathways involved in dopamine release from substantia nigra ( Fig. 1) (Ikemoto 2010). ...
Parkinson’s disease (PD) is caused due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) which leads to the depletion of dopamine in the body. The lack of dopamine is mainly due to aggregation of misfolded α-synuclein which causes motor impairment in PD. Dopamine is also required for normal retinal function and the light–dark vision cycle. Misfolded α-synuclein present in inner retinal layers causes vision-associated problems in PD patients. Hence, individuals with PD also experience structural and functional changes in the retina. Mutation in LRRK2, PARK2, PARK7, PINK1, or SNCA genes and mitochondria dysfunction also play a role in the pathophysiology of PD. In this review, we discussed the different etiologies which lead to PD and future prospects of employing non-invasive techniques and retinal changes to diagnose the onset of PD earlier.
Graphical Abstract
... Although MPTP reportedly induced cognitive dysfunction in rodents (X. Zhang et al., 2018;Han et al., 2020), this was not seen in all studies (Da Cunha et al., 2003;Ferguson et al., 2015). In the present study, MPTP did not induce significant cognitive deficits in the Y-maze test, as indicated by the ). ...
NR2D subunit-containing N-methyl-D-aspartate receptors (NMDARs) gradually disappear during brain maturation but can be recruited by pathophysiological stimuli in the adult brain. Here, we report that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication recruited NR2D subunit-containing NMDARs that generated an Mg ²⁺ -resistant tonic NMDA current (I NMDA ) in dopaminergic (DA) neurons in the midbrain of mature male mice. MPTP selectively generated an Mg ²⁺ -resistant tonic I NMDA in DA neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA). Consistently, MPTP increased NR2D but not NR2B expression in the midbrain regions. Pharmacological or genetic NR2D interventions abolished the generation of Mg ²⁺ -resistant tonic I NMDA in SNpc DA neurons, and thus attenuated subsequent DA neuronal loss and gait deficits in MPTP-treated mice. These results show that extrasynaptic NR2D recruitment generates Mg ²⁺ -resistant tonic I NMDA and exacerbates DA neuronal loss, thus contributing to MPTP-induced Parkinsonism. The state-dependent NR2D recruitment could be a novel therapeutic target for mitigating cell type-specific neuronal death in neurodegenerative diseases.
Significance Statement
NR2D subunit-containing NMDA receptors (NMDARs) are widely expressed in the brain during late embryonic and early postnatal development, and then downregulated during brain maturation and preserved at low levels in a few regions of the adult brain. Certain stimuli can recruit NR2D subunits to generate tonic persistent NMDAR currents in non-depolarized neurons in the mature brain. Our results show that MPTP intoxication recruits NR2D subunits in midbrain dopaminergic neurons, which leads to tonic NMDAR current-promoting dopaminergic neuronal death and consequent abnormal gait behavior in the MPTP mouse model of Parkinson’s disease. This is the first study to indicate that extrasynaptic NR2D recruitment all could be a target for preventing neuronal death in neurodegenerative diseases.
... The physiological relevance of nigral mGluRI-LTD is currently unknown. The nigrostriatal DA pathway contributes to goal-oriented behaviors and cognitive functions, including reward/aversion-based learning, mental flexibility, and habit formation [149][150][151][152][153][154]; thus, future research might state if mGluRI-LTD in SNpc DA neurons contributes to such brain processes. ...
Group I metabotropic glutamate receptors (mGluRI), including mGluR1 and mGluR5
subtypes, modulate essential brain functions by affecting neuronal excitability, intracellular calcium dynamics, protein synthesis, dendritic spine formation, and synaptic transmission and plasticity. Nowadays, it is well appreciated that the mGluRI-dependent long-term depression (LTD) of glutamatergic synaptic transmission (mGluRI-LTD) is a key mechanism by which mGluRI shapes connectivity in various cerebral circuitries, directing complex brain functions and behaviors, and
that it is deranged in several neurological and psychiatric illnesses, including neurodevelopmental disorders, neurodegenerative diseases, and psychopathologies. Here, we will provide an updated overview of the physiopathology of mGluRI-LTD, by describing mechanisms of induction and regulation by endogenous mGluRI interactors, as well as functional physiological implications and pathological deviations.
... DAT is selectively located at the dopaminergic neuron axon terminals concentrated in several brain regions, which leads to the prevailing selective accumulation of MPP+ and 6-OHDA in the nigrostriatal DAT-expressing dopaminergic neurons, particularly in the SNpc, found heavily involved in motor function but also in learned responses to stimuli (Da Cunha 2006). Dysfunctional mitochondria-based lesions in this region lead to primarily motor deficits but could also induce learning deficits similar to those found in PD patients (Da Cunha 2003). Intrastriatal 6-OHDA administration leads to depletion of catecholamine-expressing neurons and a selective inhibitor of noradrenergic transporter is generally used for protection of noradrenergic neurons, but even then, to a lesser extent, 6-OHDA is still capable of damaging noradrenergic neurons (Fulceri et al. 2006). ...
Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common chronic neurodegenerative disorders, characterized by motoric dysfunction or cognitive decline in the early stage, respectively, but often by both symptoms in the advanced stage. Among underlying molecular pathologies that PD and AD patients have in common, more attention is recently paid to the central metabolic dysfunction presented as insulin resistant brain state (IRBS) and altered cerebral glucose metabolism, both also explored in animal models of these diseases. This review aims to compare IRBS and alterations in cerebral glucose metabolism in representative non-transgenic animal PD and AD models. The comparison is based on the selectivity of the neurotoxins which cause experimental PD and AD, towards the cellular membrane and intracellular molecular targets as well as towards the selective neurons/non-neuronal cells, and the particular brain regions. Mitochondrial damage and co-expression of insulin receptors, glucose transporter-2 and dopamine transporter on the membrane of particular neurons as well as astrocytes seem to be the key points which are further discussed in a context of alterations in insulin signalling in the brain and its interaction with dopaminergic transmission, particularly regarding the time frame of the experimental AD/PD pathology appearance and the correlation with cognitive and motor symptoms. Such a perspective provides evidence on IRBS being a common underlying metabolic pathology and a contributor to neurodegenerative processes in representative non-transgenic animal PD and AD models, instead of being a direct cause of a particular neurodegenerative disorder.
... In such a perspective, NRGs/ErbB-dependent modulation of mGluRI-dependent LTD might have several implications in the regulation of various cognitive processes and complex behaviors dependent on the midbrain DA system. Regarding a potential link between NRG1/ErbB signaling in midbrain DA neurons and learning processes dependent on mGluR1-dependent synaptic plasticity in SNpc, it should be mentioned that ErbB4 deletion in midbrain DA neurons specifically impairs spatial/working memory [74], which is similarly affected by either systemic administration of mGluR1 antagonists or by a neurotoxin-induced lesion of SNpc [118,[125][126][127][128][129]. Therefore, despite a direct connection between nigral ErbB, mGluR1, and working memory is lacking, an interplay between mGluR1-dependent synaptic plasticity and ErbB signaling in this cognitive process related to the nigrostriatal pathway could be conceived. ...
Neuregulins (NRGs) are a family of epidermal growth factor-related proteins, acting on tyrosine kinase receptors of the ErbB family. NRGs play an essential role in the development of the nervous system, since they orchestrate vital functions such as cell differentiation, axonal growth, myelination, and synapse formation. They are also crucially involved in the functioning of adult brain, by directly modulating neuronal excitability, neurotransmission, and synaptic plasticity. Here, we provide a review of the literature documenting the roles of NRGs/ErbB signaling in the modulation of synaptic plasticity, focusing on evidence reported in the hippocampus and midbrain dopamine (DA) nuclei. The emerging picture shows multifaceted roles of NRGs/ErbB receptors, which critically modulate different forms of synaptic plasticity (LTP, LTD, and depotentiation) affecting glutamatergic, GABAergic, and DAergic synapses, by various mechanisms. Further, we discuss the relevance of NRGs/ErbB-dependent synaptic plasticity in the control of brain processes, like learning and memory and the known involvement of NRGs/ErbB signaling in the modulation of synaptic plasticity in brain’s pathological conditions. Current evidence points to a central role of NRGs/ErbB receptors in controlling glutamatergic LTP/LTD and GABAergic LTD at hippocampal CA3–CA1 synapses, as well as glutamatergic LTD in midbrain DA neurons, thus supporting that NRGs/ErbB signaling is essential for proper brain functions, cognitive processes, and complex behaviors. This suggests that dysregulated NRGs/ErbB-dependent synaptic plasticity might contribute to mechanisms underlying different neurological and psychiatric disorders.
... A considerable body of evidence shows key roles for SNc in learning and memory in addition to associated dopamine release in the control of LTP and LTD of striatal MSNs. Early investigations showed that direct stimulation of SNc during learning impairs memory retention, followed by studies directly implicating SNc in spatial/relational learning independently from hippocampal function in rodents and a potential role in reinforcement learning in humans [116][117][118][119]. ...
The molecular pathways underlying the induction and maintenance of long-term synaptic plasticity have been extensively investigated revealing various mechanisms by which neurons control their synaptic strength. The dynamic nature of neuronal connections combined with plasticity-mediated long-lasting structural and functional alterations provide valuable insights into neuronal encoding processes as molecular substrates of not only learning and memory but potentially other sensory, motor and behavioural functions that reflect previous experience. However, one key element receiving little attention in the study of synaptic plasticity is the role of neuromodulators, which are known to orchestrate neuronal activity on brain-wide, network and synaptic scales. We aim to review current evidence on the mechanisms by which certain modulators, namely dopamine, acetylcholine, noradrenaline and serotonin, control synaptic plasticity induction through corresponding metabotropic receptors in a pathway-specific manner. Lastly, we propose that neuromodulators control plasticity outcomes through steering glutamatergic transmission, thereby gating its induction and maintenance.
... Brainstem nuclei are classically the main structures involved on startle reflex and PPI (Rohleder et al., 2016;Azzopardi et al., 2018), although many studies have been suggesting that forebrain regions, including basal ganglia (BG), modulate startle reflex and PPI. The BG is a group of telencephalic, diencephalic and mesencephalic structures implicated in motor control, learning, executive functions, and emotions (Bar-Gad et al., 2003;Da Cunha et al., 2003;Faure et al., 2005;Graybiel et al., 1994;Graybiel, 2005;Haber et al., 2006;Ikegami et al., 2014;Kao and Powell, 1986 is the dorsal striatum (DS), which is composed by 95% of two subpopulations of GABAergic medium spiny neurons (MSNs) distinguished by the expression of dopaminergic receptors subtypes. The D1-MSNs (or direct pathway) express D1 dopamine receptor and project to the BG nuclei output structures, the globus pallidus internal segment -GPi (in rodents, named entopeduncular nucleus -EPN) and substantia nigra pars reticulata (SNr), inhibiting it. ...
Behavioral arrest is an essential feature of an animal's survival. Acoustic startle reflex (ASR) is an involuntary whole-body contraction of the skeletal musculature to an unexpected auditory stimulus. This strong reaction can be decreased by prepulse inhibition (PPI) phenomenon; which, for example, is important in reducing distraction during the processing of sensory input. Several brainstem regions are involved in the PPI and startle reflex, but a previous study from our laboratory showed that the main input structure of Basal Ganglia (BG) - the striatum - modulates PPI. The pallidum and nigra are connected with striatum and these brainstem structures. Here, we investigated the role of these striatum outputs in the brain regions on startle amplitude, PPI regulation, and exploratory behavior in Wistar rats. The temporary bilateral inhibition of the globus pallidus (GP) by muscimol lead to motor impairment, without disturbing startle amplitude or PPI. Similarly, inhibition of the entopeduncular nucleus (EPN) specifically disrupted the exploratory behavior. On the other hand, the substantia nigra reticulata (SNr) inhibition interfered in all measured behaviors: decreased the PPI percentage, increased ASR and impaired the locomotor activity. The nigra is a key BG output structure which projects to the thalamus and brainstem. These findings extend our previous study showing that the striatum neurons expressing D1 receptors involvement in PPI occurs via the direct pathway to SNr, but not to the pallidum which more likely occurs by its connection with the caudal pontine nucleus, superior colliculus and/or pedunculopontine nucleus pivotal structures for startle reflex modulation.
... HMGB1 expression was increased in MPTP-treated mice relative to controls 1 day post injection in the striatum and 3 days post injection in the SNpc area ( Supplementary Fig. 6a-d). In contrast, HMGB1 expression was not changed in the hippocampal area ( Supplementary Fig. 6e, f), which does not contain dopaminergic neurons, and was thus regarded as a control region [25]. Because HMGB1 upregulation was detected 1 day after MPTP injection in the striatum ( Supplementary Fig. 6a), we injected JNK and RAGE inhibitors on the same day as and 1 day after MPTP injections, and performed western blot analyses on the SNpc and striatum. ...
High-mobility group box 1 (HMGB1) is actively secreted from inflammatory cells and acts via a non-cell-autonomous mechanism to play an important role in mediating cell proliferation and migration. The HMGB1-RAGE (receptor for advanced glycation end products) axis upregulates tyrosine hydroxylase (TH) expression in response to extracellular insults in dopaminergic neurons in vitro, but little is known about HMGB1 in modulation of dopaminergic neurons in vivo. Here, using immunohistochemistry, we show that HMGB1 and RAGE expression are higher in the nigral area of MPTP (methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mice, a toxin-induced Parkinsonian mouse model, compared with saline-treated controls. HMGB1 was predominantly localized to astrocytes and may affect neighboring dopaminergic neurons in the MPTP mouse model, owing to co-localization of RAGE in these TH-positive cells. In addition, MPTP induced a decrease in TH expression, an effect that was potentiated by inhibition of c-Jun N-terminal kinase (JNK) or RAGE. Moreover, stereotaxic injection of recombinant HMGB1 attenuated the MPTP-induced reduction of TH in a Parkinsonian mouse model. Collectively, our results suggest that an increase of HMGB1, released from astrocytes, upregulates TH expression in an acute MPTP-induced Parkinsonian mouse model, thereby maintaining dopaminergic neuronal functions. High-mobility group box 1 (HMGB1) is actively secreted from inflammatory cells and acts via a non-cell autonomous mechanism to mediating cell proliferation and migration. The authors sought to determine the role of HMGB1 in modulation of dopaminergic neurons. Their results suggest that an increase of HMGB1, released from astrocytes, upregulates TH expression in a Parkinsonian mouse model, thereby maintaining dopaminergic neuronal functions.
... Se ha explorado la posibilidad de que el efecto protector descrito también se manifieste a través de la interferencia con el funcionamiento de otros núcleos cerebrales que participan en procesos mnemónicos. Sería de esperar que la sustancia negra compartiera algunas características funcionales con el estriado, ya que está conectada directa y bidireccionalmente con él, además de que es una estructura que indudablemente participa en la formación de la memoria [54][55][56][57][58]. ...
... In addition to the glutamatergic inputs of the hippocampus, it receives dopaminergic, noradrenergic, serotonergic, and cholinergic inputs [17][18][19][20]. The hippocampus receives dopaminergic inputs from the substantia nigra (SN) [21], and these inputs are associated with cognitive function and adult hippocampal neurogenesis [22,23]. Moreover, the pathogenesis of AD is, in part, associated with dopaminergic neuronal loss and deficits [24]. ...
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline and neurodegeneration in the hippocampus. Despite the pathological importance of the hippocampal degeneration in AD, little topographical evidence exists of impaired hippocampal connectivity in patients with AD. To investigate the anatomical connections of the hippocampus, we injected the neurotracer 1,1′-dioctadecyl-3,3,3′3,3′-tetramethyl-indocarbocyanine perchlorate (DiI) into the hippocampi of 5XFAD mice, which were used as an animal model of AD. In wild-type controls, DiI-containing cells were found in the entorhinal cortex, medial septum, locus coeruleus, dorsal raphe, substantia nigra pars compacta, and olfactory bulb. Hippocampal inputs were decreased in multiple brain regions in the 5XFAD mice compared to wild-type littermate mice. These results are the first to reveal alterations at the cellular level in hippocampal connectivity in the brains of 5XFAD mice. These results suggest that anatomical mapping of hippocampal connectivity will elucidate new pathogenic mechanisms and therapeutic targets for AD treatment.
Electronic supplementary material
The online version of this article (10.1007/s12035-018-0918-y) contains supplementary material, which is available to authorized users.
... The nigrostriatal pathway is of remarkable importance for memory and other non-motor symptoms of PD [57][58][59]. Regarding recognition memory, different studies demonstrate that SNpc lesioning leads to impairment in this type of memory, corroborating our results [8,10]. Dos Santos and colleagues [33] reported impaired object recognition memory 22 days after nigral rotenone infusion, which leads us to believe that this model promotes a somewhat long-term cognitive decline [33]. ...
Cognitive impairment is an important non-motor symptom of Parkinson's disease (PD). The neuronal death in nigrostriatal pathway is the main factor for motor symptoms and recent studies indicate a possible influence in non-motor symptoms as well. The pedunculopontine tegmental nucleus (PPT) and basal ganglia are closely related anatomically and functionally and, since they are affected by neurodegeneration in PD, they might be involved in recognition memory. To investigate this, we promoted an ibotenic acid lesion within the PPT or a rotenone lesion within substantia nigra pars compacta (SNpc) of Wistar rats, followed by 24h of REM sleep deprivation (REMSD). Then, we administered a dopaminergic D2 receptor agonist (piribedil, 3μg/μl), antagonist (raclopride, 10μg/μl) or vehicle (dimethylsulfoxide) directly in the striatum and the animals were submitted to the object recognition test (ORT). We observed that raclopride administration impaired object recognition memory as well as rotenone and ibotenic acid lesion. Interestingly, REMSD reversed the deleterious effects induced by these drugs. Also, raclopride administration after rotenone lesion allowed the animal to explore the new object for a longer time compared to the familiar object, suggesting that raclopride has a dual effect, dependent of the treatments. These findings suggest a role for PPT, SNpc and striatum in recognition memory and points the D2 receptors modulation and REMSD as possible targets for cognitive deficits in Parkinson's disease.
... This circuitry was likely intact in the present study. More complete nigral DA lesions may impair spatial navigation and strategy learning (Da Cunha et al., 2003;Hefco et al., 2003), This document is copyrighted by the American Psychological Association or one of its allied publishers. ...
Degeneration of the nigrostriatal dopaminergic system in Parkinson's disease (PD) causes motor dysfunction and cognitive impairment, but the etiology of the cognitive deficits remains unclear. The present study investigated the behavioral effects of partial lesions of the nigrostriatal dopamine (DA) pathway. Rats received bilateral infusions of either 6-hydroxydopamine (6-OHDA) or vehicle into the dorsolateral striatum and were tested in spatial and procedural learning tasks. Compared with intact rats, DA-depleted rats were impaired when the first task they learned required egocentric responses. Intact rats that received prior training on a spatial task were impaired while learning a subsequent body-turn task, suggesting that prior spatial training may compete with egocentric learning in intact but not DA-depleted rats. Spatial discrimination, reversal learning, and switching between allocentric and egocentric strategies were similar in both groups. The results suggest that DA loss that is not associated with gross motor pathology temporarily impairs egocentric, but not allocentric, learning or subsequent behavioral flexibility. (PsycINFO Database Record
... Additionally, DA serves to expand or contract the width of information held in working memory buffers in networks of the prefrontal cortex [66]. Substantia nigra pars compacta (SNpc) is an indispensable section of a memory system which is not dependent of the hippocampal memory system [67]. MPTP (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine) is a well-identified neurotoxin that destroys dopaminergic neurons [68] and has been used since decades to study models of PD. ...
Animal models for learning and memory have significantly contributed to novel strategies for drug development and hence are an imperative part in the assessment of therapeutics. Learning and memory involve different stages including acquisition, consolidation, and retrieval and each stage can be characterized using specific toxin. Recent studies have postulated the molecular basis of these processes and have also demonstrated many signaling molecules that are involved in several stages of memory. Most insights into learning and memory impairment and to develop a novel compound stems from the investigations performed in experimental models, especially those produced by neurotoxins models. Several toxins have been utilized based on their mechanism of action for learning and memory impairment such as scopolamine, streptozotocin, quinolinic acid, and domoic acid. Further, some toxins like 6-hydroxy dopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and amyloid-β are known to cause specific learning and memory impairment which imitate the disease pathology of Parkinson’s disease dementia and Alzheimer’s disease dementia. Apart from these toxins, several other toxins come under a miscellaneous category like an environmental pollutant, snake venoms, botulinum, and lipopolysaccharide. This review will focus on the various classes of neurotoxin models for learning and memory impairment with their specific mechanism of action that could assist the process of drug discovery and development for dementia and cognitive disorders.
... The 23 % reduction seen here, however, is below the threshold of DA loss required to cause learning deficits. Previous studies have observed that dStr DA decreases of \60 % do not alter allocentric learning (Miyoshi et al. 2002;Da Cunha et al. 2003). Similarly, we find that 52 % DA loss in the DMS does not cause CWM or MWM deficits (unpublished observations). ...
The nucleus accumbens (Nacc) and medial prefrontal cortex (mPFC) receive dopaminergic innervation from the ventral tegmental area and are involved in learning. Male rats with 6-hydroxydopamine (6-OHDA)-induced dopaminergic and noradrenergic reductions in the Nacc or mPFC were tested for allocentric and egocentric learning to determine their role in these forms of neuroplasticity. mPFC dopaminergic and noradrenergic reductions did not result in changes to either type of learning or memory. Nacc dopaminergic and noradrenergic reductions resulted in allocentric learning and memory deficits in the Morris water maze (MWM) on acquisition, reversal, and probe trials. MWM cued performance was also affected, but straight-channel swim times and swim speed during hidden platform trials in the MWM were not affected. Nacc dopaminergic and noradrenergic reductions also impaired egocentric learning in the Cincinnati water maze (CWM). Nacc-lesioned animals tested in the CWM in an alternate path through the maze were not significantly affected. 6-OHDA injections in the Nacc resulted in 63 % dopamine and 62 % norepinephrine reductions in the Nacc and 23 % reductions in adjacent dorsal striatum. 6-OHDA injections in the mPFC resulted in 88 % reductions in dopamine and 59 % reductions in norepinephrine. Hence, Nacc dopamine and/or norepinephrine play a role in egocentric and allocentric learning and memory, while mPFC dopamine and norepinephrine do not.
... The accuracy performance was only impaired in the cued version of the task. This mirrors the result reported by Cunha et al. (2003) where lesion of substantia nigra pars compacta also selectively impaired the cue version of the water maze task. ...
Rats learn to navigate to a specific location faster in a familiar environment (Keith and Mcvety
1988). It has been proposed that place learning does not require specific reward signals, but
rather, that it occurs automatically. One of the strongest pieces of evidence for the automatic
nature of place learning comes from the observation that place and head direction cells reference
their receptive fields to prominent landmarks in an environment without needing a reward
signal (O’Keefe and Conway 1978; Taube et al. 1990b). It has also been proposed that an
allocentric representation of an environment would be bound to the landmarks with the greatest
relative stability to guide its orientation (O’Keefe and Nadel 1978). The first two parts of
this thesis explore whether place and head direction cells automatically use the most coherent
landmarks for orientation. Head direction cells have been shown to orient their preferred firing
directs coherently when being exposed to conflicting landmarks in an environment (Yoganarasimha
et al. 2006). A model of head direction cells was thus used to explore the necessary
mechanisms required to implement an allocentric system that selects landmarks based on their
relative stability. We found that the simple addition of Hebbian projections combined with
units representing the orientation of landmarks to the head direction cell system is sufficient
for the system to exhibit such a capacity. We then recorded both entorhinal head direction cells
and CA1 place cells and at the same time subjected the rats to repeated experiences of landmark
conflicts. During the conflicts a subset of landmarks always maintained a fixed relative
relationship with each other. We found that the visual landmarks retained their ability to control
the place and head direction cells even after repeated experience of conflict and that the simultaneously
recorded place cells exhibited coherent representations between conflicts. However,
the ’stable landmarks’ did not show significantly greater control over the place and head direction
cells when comparing to the unstable landmarks. This argues against the hypothesis that
the relative stability between landmarks is encoded automatically. We did observe a trend that,
with more conflict experience, the ’stable landmarks’ appeared to exert greater control over the
cells.
The last part of the thesis explores whether goal sensitive cells (Ainge et al. 2007a) discovered
from CA1 of hippocampus are developed due to familiarity with the environment or from
the demands for rats to perform a win-stay behaviour. We used the same win-stay task as in
Ainge et al. and found that there were few or no goal sensitive cells on the first day of training.
Subsequent development of goal sensitive activity correlated significantly with the rat’s performance
during the learning phase of the task. The correlation provides support to the hypothesis
that the development of goal sensitive cells is associated to the learning of the win-stay task
though it does not rule out the possibility that these goal sensitive cells are developed due to
the accumulated experience on the maze.
In summary, this thesis explores what kind of spatial information is encoded by place and head direction cells and finds that relative stability between landmarks without a reward signal
is not automatically encoded. On the other hand, when additional information is required to
solve a task, CA1 place cells adapt their spatial code to provide the necessary information to
guide successful navigation.
... Such a mechanism may underlie the decrease in distance moved in the probe trial, and the reduced rearing behaviour observed in the present study. While the standard place-learning MWM task is thought to be hippocampal-dependent, the cued test requires stimulus-response learning and recent evidence has shown that cuedtest performance is disrupted by lesion of the substantia nigra [54,55]. Thus, the finding of impaired functionality of cannabinoid receptors in the substantia nigra in this study may be a contributory factor in the impaired cued-test learning in the STZ-treated animals. ...
Diabetes, and associated diabetic neuropathic pain, impact negatively on cognitive function. However, the underlying mechanisms remain poorly understood. This study investigated neuropathic pain-related behaviour and cognitive function in the rat streptozotocin (STZ) model of diabetes, and assessed cannabinoid1 (CB1) receptor functionality in discrete brain regions. Male Lister-Hooded rats received STZ (60 mg/kg s.c.) or vehicle. Sensory responses were assessed in von Frey and Hargreaves tests. Cognitive, motor and sensorimotor functions were assessed using novel object recognition and Morris water maze tasks. CB1 receptor functionality was assessed by [35S]GTPγS (guanosine 5'-O-[gamma-thio]triphosphate) autoradiography. STZ treatment was associated with mechanical allodynia and thermal hypoalgesia. Novel object recognition was unaltered in diabetic rats. STZ treatment was associated with impaired performance in the Morris water maze acquisition phase, but there were no differences in memory retrieval in the probe trial. Stimulus-response learning in the water maze cued trial was also disrupted in STZ-treated rats, possibly indicating sensorimotor deficits. CB1 receptor agonist-stimulated [35S]GTPγS binding was attenuated in the substantia nigra of STZ-treated rats but unaltered in the hippocampus. In conclusion, STZ treatment as a model of diabetic neuropathy was associated with specific functional deficits in the MWM, effects which may be related to altered CB1 receptor functionality in the substantia nigra.
... These paradigms have been used to validate the theory of multiple memory systems by observing the effect of localised lesions (e.g. in hippocampus or dorsal striatum) in the preference for locale or S-R strategies (Whishaw et al., 1987;Packard et al., 1989;Pearce et al., 1998;Da Cunha et al., 2003). As mentioned, substantial evidence supports the idea that the hippocampus mediates spatial learning 2 , whereas the dorsal striatum is involved in S-R learning (See Redish (1999); Packard and Knowlton (2002); White and McDonald (2002) for reviews). ...
Animals behave in different ways depending on the specific task they are required to solve. In certain cases, if a cue marks the goal location, they can rely on simple stimulusresponse associations. In contrast, other tasks require the animal to be endowed with a representation of space. Such a representation (i.e. cognitive map) allows the animal to locate itself within a known environment and perform complex target-directed behaviour. In order to efficiently perform, the animal not only should be able to exhibit these types of behaviour, but it should be able to select which behaviour is the most appropriate at any given task conditions. Neurophysiological and behavioural experiments provide important information on how such processes may take place in the rodent's brain. Specifically, place- and orientation sensitive cells in the rat Hippocampus have been interpreted as a neural substrate for spatial abilities related to the theory of the cognitive map proposed in the late 1940s by Tolman. Moreover, recent dissociation experiments using selectively located lesions, as well as pharmacological studies have shown that different brain regions may be involved in different types of behaviour. Accordingly, one memory system involving the hippocampus and the ventral striatum would be responsible for cognitive navigation, while navigation based on stimulus-response associations would be mediated by the dorsolateral striatum. Based on these studies, the aim of this work is to develop a neural network model of the spatial abilities of the rat. The model, based on functional properties and anatomical inter-connections of the brain areas involved in spatial learning should be able to establish a distributed representation of space composed of place-sensitive units. Such a representation takes into account both internal and external sensory information, and the model reproduces physiological properties of place cells such as changes in their directional dependence. Moreover, the spatial representation may be used to perform cognitive navigation. Modelled place cells drive an extra-hippocampal population of action-coding cells, allowing the establishment of place-response associations. These associations encoded in synaptic connections between place- and action-cells are modified by means of reinforcement learning. In a similar way, simple sensory input can be used to establish stimulus-response associations. These associations are encoded in a different set of action cells which corresponds to a different neural substrate encoding for non-cognitive navigation strategies (i.e. taxon or praxic). Both cognitive and non-cognitive navigation strategies compete for action control to determine the actual behaviour of the agent. Tests of the performance of the model show that it is able to establish a representation of space, and modelled place cells reproduce some physiological properties of their biological counterparts. Furthermore, the model reproduces goal-based behaviour based on both cognitive and non-cognitive strategies as well as behaviour in conflicting situations reported in experimental studies in animals.
... These neurons were specifically labeled by tyrosine hydroxylase (TH). 21,22 We found no significant change in the number of TH-positive neurons in the substantia nigra pars compacta of bf mice at 10 mo of age (Fig. 1F). However, the number of Purkinje cells in the cerebellum, labeled by CALB1/calbindin, was decreased in bf mice at 6 mo of age (Fig. 1G). ...
The HOPS (homotypic fusion and protein sorting) complex functions in endocytic and autophagic pathways in both lower eukaryotes and mammalian cells through its involvement in fusion events between endosomes and lysosomes or autophagosomes and lysosomes. However, the differential molecular mechanisms underlying these fusion processes are largely unknown. Buff (bf) is a mouse mutant that carries an Asp251-to-Glu point mutation (D251E) in the VPS33A protein, a tethering protein and a core subunit of the HOPS complex. Bf mice showed impaired spontaneous locomotor activity, motor learning, and autophagic activity. Although the gross anatomy of the brain was apparently normal, the number of Purkinje cells was significantly reduced. Furthermore, we found that fusion between autophagosomes and lysosomes was defective in bf cells without compromising the endocytic pathway. The direct association of mutant VPS33AD251E with the autophagic SNARE complex, STX17 (syntaxin 17)-VAMP8-SNAP29, was enhanced. In addition, the VPS33AD251E mutation enhanced interactions with other HOPS subunits, namely VPS41, VPS39, VPS18, and VPS11, except for VPS16. Reduction of the interactions between VPS33AY440D and several other HOPS subunits led to decreased association with STX17. These results suggest that the VPS33AD251E mutation plays dual roles by increasing the HOPS complex assembly and its association with the autophagic SNARE complex, which selectively affects the autophagosome-lysosome fusion that impairs basal autophagic activity and induces Purkinje cell loss.
... MPTP lesioning in the substantia nigra pars compacta (SNc) results in a pathophysiology similar to that seen in PD [17,18] and causes motor dysfunction [19,20] and hyperactivation in the glutamatergic system [21]. In addition, cognitive impairment has been observed in MPTP-lesioned rats, which shows disturbances of learning in the two-way active avoidance test [22] and the Morris water maze test [20,22,23]. Our previous studies demonstrated that MPTP-lesioned rats show memory and recognition deficits, thus serving as a model of PD dementia (PDD) [24][25][26][27]. ...
... It is unlikely that greater DA loss would have resulted in a MWM allocentric learning impairment. Allocentric learning deficits in the MWM require a threshold of about 60% neostriatal DA depletion (Whishaw and Dunnett, 1985, Lindner et al., 1999, Miyoshi et al., 2002, Da Cunha et al., 2003, Mura and Feldon, 2003, De Leonibus et al., 2007, Braun et al., 2012, a level of reduction exceeded in the present experiments. Since DA loss in the DLS and DMS lesioned groups surpassed this level of reduction, it suggests that more widespread neostriatum DA loss is necessary before allocentric learning deficits are observed rather than greater subregional loss. ...
... One possible explanation is that the lidocaine concentration used in the study was too low. However, we injected a previously tested concentration of 2% that has already shown to be effective (Da Cunha et al., 2003). Also, it could be possible that such a short inhibition of SNc was not enough to change cerebellar activity. ...
The suggestion of an anatomical and functional relationship between the basal ganglia and cerebellum is recent. Traditionally, these structures were considered as neuronal circuits working separately to organize and control goal-directed movements and cognitive functions. However, several studies in rodents and primates have described an anatomical interaction between cortico-basal and cortico-cerebellar networks. Most importantly, functional changes have been observed in one of these circuits when altering the other one. In this context, we aimed to accomplish an extensive description of cerebellar activation patterns using cFOS expression (cFOS-IR) after acute and chronic manipulation of dopaminergic activity. In the acute study, substantia nigra pars compacta (SNc) activity was stimulated or suppressed by intra cerebral administration of picrotoxin or lidocaine, respectively. In addition, we analysed cerebellar activity after the induction of a parkinsonism model, the tremulous jaw movements. In this model, tremulous jaw movements were induced in male rats by IP chronic administration of the dopamine antagonist haloperidol (1.5 mg /kg). Acute stimulation of SNc by picrotoxin increased cFOS-IR in the vermis and cerebellar hemispheres. However, lidocaine did produce any effect. After 14 days of haloperidol treatment, the vermis and cerebellar hemispheres showed an opposite regulation of cFOS expression. Chronic dopaminergic antagonism lessened cFOS expression in the vermis but up-regulated such expression in the cerebellar hemisphere. Overall, the present data indicate a very close functional relationship between the basal ganglia and the cerebellum and they may allow a better understanding of disorders in which there are dopamine alterations.
... Nevertheless, it has been shown that small variations in the levels of monoamines induced by reserpine can promote cognitive deficits in the absence of the motor impairments [27,28] . In addition , previous studies have shown that the acute administration of low doses of neurotoxins may cause cognitive impairments similar to that occur in early stages of PD [18,72,757677. Moreover, other findings [72,78–81] demonstrated that nearly 40% depletion of striatal DA is capable of causing deficits in memory tasks, while the motor impairments are visible only when there is a reduction of 60–80% of dopaminergic neurons [2,39]. ...
... γ-Synuclein inactivation did not affect spatial learning in the Morris water maze although γ-synuclein is highly expressed in the brain areas involved in spatial learning [35] and its inactivation was shown to cause developmental deficit in the number of dopamine neurons in the midbrain [27,31] an essential component for a water maze cued task learning [36]. We also did not reveal alterations in spatial memory of γ-KO mice. ...
Background
Gamma-synuclein is a member of the synuclein family of cytoplasmic, predominantly neuron-specific proteins. Despite numerous evidences for the importance of gamma-synuclein in the control of monoamine homeostasis, cytoskeleton reorganization and chaperone activity, its role in the regulation of cognitive behavior still remain unknown. Our previous study revealed that gamma-synuclein knockout mice are characterized by high habituation scores. Since a number of processes including spatial memory of the environment may affect habituation, in the present study we have carried out behavioral evaluation of spatial and working memory in gamma-synuclein knockout mice.
Results
Inactivation of gamma-synuclein gene led to the improvement of working memory in mice as revealed by passive and active avoidance tests. At the same time behavioral tests, designed to assess spatial learning and memory (Morris water maze and Object location tests), showed no differences between gamma-synuclein knockouts and wild type mice.
Conclusions
These findings indicate that young mice with targeted inactivation of gamma-synuclein gene have improved working memory, but not spatial learning and memory. Our results suggest that gamma-synuclein is directly involved in the regulation of cognitive functions.
... These SNc oscillations ensure a continuous supply of dopamine to the striatum, significant for its normal functioning. Also, regular oscillations in SNc neurons switch to a bursting mode in response to a stimulus, a behaviour that is associated with spatial learning and temporal processing (Da Cunha et al, 2003; Matell and Meck, 2000 ). Further, these neurons are extensively arborised to provide uniform percolation of dopamine in the striatum (Matsuda et al, 2009). ...
Spontaneous oscillations in the mid-brain dopaminergic neurons are an important feature of motor control. The degeneration of these neurons is involved in movement disorders, particularly Parkinson’s Disease. Modelling of this activity is an important part of developing an understanding of the pathogenic process. We develop a mathematical paradigm to describe this activity with a single compartment approach and a CellML version is made publicly available. The model explicitly describes the dynamics of the transmembrane potential with changes in the levels of important cations and is consistent with two major observations in the literature regarding its behaviour in the presence of channel blockers. Stability of the model behaviour is determined from the properties of its Monodromy matrix. We also discuss from the perspective of energy, a pharmacological intervention suggested in the treatment of Parkinson’s Disease.
... The involvement of the SN in memory processes is well documented (Routtenberg and Holzman, 1973; Ambrogi- Lorenzini et al., 1994; DaCunha et al., 2003; D í az del Guante et al., 2004). Kim and Routtenberg (1976) showed that injection of picrotoxin into the SN after IA training disrupted retention. ...
Abstract Most of the work related to the neurobiological basis of memory has been guided by the memory consolidation theory, which was derived from the seminal work of Müller and Pilzecker that was published over a century ago. This theory proposes that the transfer from short- to long-term memory is mediated by a process called consolidation, and while consolidation is taking place, the information to be stored is in a labile state. A great deal of experimentation has given strong support to this proposal, as it has been found repeatedly that interference with neural activity shortly after a learning experience impedes durable retention of that experience. A growing body of evidence, however, indicates that intense emotional experiences prevent memory loss induced by amnesic treatments, even when these treatments are administered intracerebrally shortly after the learning experience. This evidence implies that the memory consolidation theory cannot account for long-term memory formation when neural activity is disrupted while consolidation should be taking place, and it calls for new hypotheses to account for these findings.
... Pathways arising from dopaminergic midbrain nuclei also innervate the prefrontal and insular cortices, several thalamic and hypothalamic nuclei and the monoaminergic nuclei of the brain stem, superior colliculus, reticular formation and periaqueductal gray, all having important roles in regulating arousal as well as affective and cognitive processes. In addition, the PC is important in spatial learning and some studies have suggested its involvement in a response-based memory system that utilizes a dorsostriatal pathway and may function independently of the hippocampus (Da Cunha et al., 2003). In addition, the VTA is strongly involved in the reward circuitry of the brain, with important roles in cognition and motivation (Margolis et al., 2006). ...
Aging is, by far, the greatest risk factor for most neurodegenerative diseases. In non-diseased conditions, normal aging can also be associated with declines in cognitive function that significantly affect quality of life in the elderly. It was recently shown that inhibition of Mammalian TOR (mTOR) activity in mice by chronic rapamycin treatment extends lifespan, possibly by delaying aging {Harrison, 2009 #4}{Miller, 2011 #168}. To explore the effect of chronic rapamycin treatment on normal brain aging we determined cognitive and non-cognitive components of behavior throughout lifespan in male and female C57BL/6 mice that were fed control- or rapamycin-supplemented chow. Our studies show that rapamycin enhances cognitive function in young adult mice and blocks age-associated cognitive decline in older animals. In addition, mice fed with rapamycin-supplemented chow showed decreased anxiety and depressive-like behavior at all ages tested. Levels of three major monoamines (norepinephrine, dopamine and 5-hydroxytryptamine) and their metabolites (3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindolacetic acid) were significantly augmented in midbrain of rapamycin-treated mice compared to controls. Our results suggest that chronic, partial inhibition of mTOR by oral rapamycin enhances learning and memory in young adults, maintains memory in old C57BL/6J mice, and has concomitant anxiolytic and antidepressant-like effects, possibly by stimulating major monoamine pathways in brain.
Introduction-Stress is defined as a reaction of the brain to external factors or internal situations, and which in turn controls the behavioral responses according to the situation. The neurons of the cognitive areas of the brain like cingulate gyrus and substantia nigra, which are mainly involved in memory and decision making are susceptible to stress. However, the magnitude of the effect depends upon two crucial factors the duration and nature of stress. Method- To investigate this,on adult Albino mice two type of stress procedure that is restraint and foot shock stress, was applied for the duration of 5days (short duration) and 21 days (long duration).In restraint stress mice were stressed 6 hrs/ day in a wire mesh restrainer while in foot shock stress mice were given intermittent electric foot shock using foot shock apparatus for three hours per day for the duration of 5 and 21 days. Result-The results of the behavioral tests showed that the severity of memory and learning deficit increased with the duration of stress irrespective of nature of stress. Severe neurodegenerative changes seen in anterior cingulate gyrus and substantia nigra on prolonged exposure to stress, hypertrophy of adrenal cortex and gastric ulcers observed in stressed animals compared to their age matched controls confirms the effect of stress. Conclusion- The study reveals the effect of stress on structural and functional plasticity, how it disturbs the cognitive process like learning and memory, how it results in behavioral deficits and will help us in understanding the neurobiology of the psychiatric disorders.
Sex steroid hormones like estradiol (E2) and progesterone (P4) guide the sexual organization and activation of the developing brain and control female reproductive behavior throughout the lifecycle; importantly, these hormones modulate functional activity of not just the endocrine system, but most of the nervous system including the brain reward system. The effects of E2 and P4 can be seen in the processing of and memory for rewarding stimuli and in the development of compulsive reward-seeking behaviors like those seen in substance use disorders. Women are at increased risk of developing substance use disorders; however, the origins of this sex difference are not well understood and therapeutic interventions targeting ovarian hormones have produced conflicting results. This article reviews the contribution of the E2 and P4 in females to functional modulation of the brain reward system, their possible roles in origins of addiction vulnerability, and the development and treatment of compulsive reward-seeking behaviors.
Memory and motor deficits are commonly identified in Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is transformed to MPP+ via monoamine oxidase B (MAOB), which causes oxidative stress and destroys dopaminergic (DA) neurons in substantia nigra pars compacta (SNc) and is widely used to create animal models of PD. However, to-date, a comprehensive analysis of the MPTP effects on various aspects of PD does not exist. Here, we provide a systematic review and meta-analysis on the MPTP effects on memory and motor functions by analyzing 51 studies on more than one thousand animals mainly including rats and mice. The results showed that in addition to motor functions such as coordination, balance and locomotor activity, MPTP significantly affects various mnemonic processes including spatial memory, working memory, recognition memory, and associative memory compared with the control group with some differences between systemic and intra-nigral injections on spatial memory, familiar object recognition, and anxiety-like behaviors. Nevertheless, our analysis failed to find systematic relationship between MPTP injection protocol parameters reported and the extent of the induced PD symptoms that can be a cause of concern for replicability of MPTP studies.
Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory and a general cognitive decline leading to dementia. AD is characterized by changes in the behavior of the genome and can be traced across multiple brain regions and cell types. It is mainly associated with β-amyloid deposits and tau protein misfolding, leading to neurofibrillary tangles. In recent years, however, research has shown that there is a high complexity of mechanisms involved in AD neurophysiology and functional decline enabling its diverse presentation and allowing more questions to arise. In this study, we present a computational approach to facilitate brain region-specific analysis of genes and biological processes involved in the memory process in AD. Utilizing current genetic knowledge we provide a gene set of 265 memory-associated genes in AD, combinations of which can be found co-expressed in 11 different brain regions along with their functional role. The identified genes participate in a spectrum of biological processes ranging from structural and neuronal communication to epigenetic alterations and immune system responses. These findings provide new insights into the molecular background of AD and can be used to bridge the genotype–phenotype gap and allow for new therapeutic hypotheses.
The most common features of Parkinson’s disease (PD) are motor impairments, but many patients also present depression and memory impairment. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to be effective in patients with treatment-resistant major depression. Thus, the present study evaluated the action of ketamine on memory impairment and depressive-like behavior in an animal model of PD. Male Wistar rats received a bilateral infusion of 6 μg/side 6-hydroxydopamine (6−OHDA) into the substantia nigra pars compacta (SNc). Short-term memory was evaluated by the social recognition test, and depressive-like behaviors were evaluated by the sucrose preference and forced swimming tests (FST). Drug treatments included vehicle (i.p., once a week); ketamine (5, 10 and 15 mg/kg, i.p., once a week); and imipramine (20 mg/kg, i.p., daily). The treatments were administered 21 days after the SNc lesion and lasted for 28 days. The SNc lesion impaired short-term social memory, and all ketamine doses reversed the memory impairment and anhedonia (reduction of sucrose preference) induced by 6-OHDA. In the FST, 6-OHDA increased immobility, and all doses of ketamine and imipramine reversed this effect. The anti-immobility effect of ketamine was associated with an increase in swimming but not in climbing, suggesting a serotonergic effect. Ketamine and imipramine did not reverse the 6-OHDA-induced reduction in tyrosine hydroxylase immunohistochemistry in the SNc. In conclusion, ketamine reversed depressive-like behaviors and short-term memory impairment in rats with SNc bilateral lesions, indicating a promising profile for its use in PD patients.
Astrocytes represent central regulators of brain glucose metabolism and neuronal function. They have recently been shown to adapt their function in response to alterations in nutritional state through responding to the energy state-sensing hormones leptin and insulin. Here, we demonstrate that glucagon-like peptide (GLP)-1 inhibits glucose uptake and promotes β-oxidation in cultured astrocytes. Conversely, postnatal GLP-1 receptor (GLP-1R) deletion in glial fibrillary acidic protein (GFAP)-expressing astrocytes impairs astrocyte mitochondrial integrity and activates an integrated stress response with enhanced fibroblast growth factor (FGF)21 production and increased brain glucose uptake. Accordingly, central neutralization of FGF21 or astrocyte-specific FGF21 inactivation abrogates the improvements in glucose tolerance and learning in mice lacking GLP-1R expression in astrocytes. Collectively, these experiments reveal a role for astrocyte GLP-1R signaling in maintaining mitochondrial integrity, and lack of GLP-1R signaling mounts an adaptive stress response resulting in an improvement of systemic glucose homeostasis and memory formation.
Cellular polarity is crucial for brain development and morphogenesis. Lethal giant larvae 1 (Lgl1) plays a crucial role in the establishment of cell polarity from Drosophila to mammalian cells. Previous studies have found the importance of Lgl1 in the development of cerebellar, olfactory bulb, and cerebral cortex. However, the role of Lgl1 in hippocampal development during the embryonic stage and function in adult mice is still unknown. In our study, we created Lgl1‐deficient hippocampus mice by using Emx1‐Cre mice. Histological analysis revealed that the Emx1‐Lgl1−/− mice exhibited reduced size of the hippocampus with severe malformations of hippocampal cytoarchitecture. These defects mainly originated from the disrupted hippocampal neuroepithelium, including increased cell proliferation, abnormal interkinetic nuclear migration, reduced differentiation, increased apoptosis, gradual disruption of adherens junctions, and abnormal neuronal migration. The radial glial scaffold was disorganized in the Lgl1‐deficient hippocampus. Thus, Lgl1 plays a distinct role in hippocampal neurogenesis. In addition, the Emx1‐Lgl1−/− mice displayed impaired behavioral performance in the Morris water maze and fear conditioning test. • Lethal giant larvae 1 (Lgl1) inactivation reduced the size of and deformed the hippocampus. • Lgl1 affected the number of hippocampal progenitor cells and neuronal migration. • Conditional removal of Lgl1 caused neurobehavioral deficiencies in cognitive performance in Morris water maze and the contextual fear conditioning tasks.
Increasing evidence demonstrates that the neurotrophic factor Neuregulin 1 (NRG1) and its receptors, ErbB tyrosine kinases, modulate midbrain dopamine (DA) transmission. We have previously reported that NRG1/ErbB signalling is essential for proper metabotropic glutamate receptors 1 (mGluR1) functioning in midbrain DA neurons, thus the functional interaction between ErbB receptors and mGluR1 regulates neuronal excitation and in vivo striatal DA release.
While it is widely recognized that mGluR1 play a pivotal role in long-term modifications of synaptic transmission in several brain areas, specific mGluR1-dependent forms of synaptic plasticity in substantia nigra pars compacta (SNpc) DA neurons have not been described yet.
Here, firstly we aimed to detect and characterize mGluR1-dependent glutamatergic long-term depression (LTD) in SNpc DA neurons. Secondly, we tested the hypothesis that endogenous ErbB signalling, by affecting mGluR1, fine-tunes glutamatergic synaptic plasticity in DA cells.
We found that either pharmacological or synaptic activation of mGluR1 causes a LTD of AMPAR-mediated transmission in SNpc DA neurons from mice and rat slices, which is reliant on endogenous NRG1/ErbB signalling. Indeed, LTD is counteracted by a broad spectrum ErbB inhibitor. Moreover, the intracellular injection of pan-ErbB- or ErbB2 inhibitors inside DA neurons reduces mGluR1-dependent LTD, suggesting an involvement of ErbB2/ErbB4-containing receptors. Interestingly, exogenous NRG1 fosters LTD expression during minimal mGluRI activation.
These results enlarge our cognizance on mGluR1 relevance in the induction of a novel form of long-term synaptic plasticity in SNpc DA neurons and describe a new NRG1/ErbB-dependent mechanism shaping glutamatergic transmission in DA cells. This might have important implications either in DA-dependent behaviors and in learning/memory processes or in DA-linked diseases.
Spatial memory deficits are a common hallmark of psychiatric conditions, possibly due to a genetic predisposition. Thus, unravelling the relationship between genes and memory might suggest novel therapeutic targets and pathogenetic pathways. Genetic deletions are known to lead to memory deficits (post-deletion "forgetfulness" genes, PDF), or, in few instances to improve spatial memory (post-deletion "hypermnesic" genes, PDH). To assess this topic, we performed a meta-analytic approach on memory behavior in knock-out mice. We screened 300 studies from PubMed and retrieved 87 genes tested for possible effects on spatial memory. This database was crossed with the Allen Brain Atlas (brain distribution) and the Enrichr (gene function) databases. The results show that PDF genes have higher expression level in several ventral brain structures, particularly the encephalic trunk and in the hypothalamus. Moreover, part of these genes are implicated in synaptic functions. Conversely, the PDH genes are associated to G-protein coupled receptors downstream signalling. Some candidate drugs were also found to interfere with some of the PDH genes, further suggesting that this approach might help in identifying drugs to improve memory performance in psychiatric conditions.
Parkinson’s disease (PD) is well known for motor deficits such as bradykinesia. However, patients often experience additional deficits in working memory, behavioral selection, decision-making and other executive functions. Like other features of PD, the incidence and severity of these cognitive symptoms differ in males and females. However, preclinical models have not been used to systematically investigate the roles that sex or sex hormones may play in these complex signs. To address this, we used a Barnes maze spatial memory paradigm to compare the effects of a bilateral nigrostriatal dopamine lesion model of early PD on cognitive behaviors in adult male and female rats and in adult male rats that were gonadectomized or gonadectomized and supplemented with testosterone or estradiol. We found that dopamine lesions produced deficits in working memory and other executive operations, albeit only in male rats where circulating androgen levels were physiological. In males where androgen levels were depleted, lesions produced no additional Barnes maze deficits and attenuated those previously linked to androgen deprivation. We also found that while most measures of Barnes maze performance were unaffected by dopamine lesions in the females, lesions did induce dramatic shifts from their preferred use of thigmotactic navigation to the use of spatially guided place strategies similar to those normally preferred by males. These and other sex- and sex hormone-specific differences in the effects of nigrostriatal dopamine lesions on executive function highlight the potential of gonadal steroids as protective and/or therapeutic for the cognitive symptoms of PD. However, their complexity also indicates the need for a more thorough understanding of androgen and estrogen effects in guiding the development of hormone therapies that might effectively address these non-motor signs.
Introduction: The reduction of dopamine level caused by neurodegenerative diseases such as Parkinson's disease (PD) may reduce the production of new neurons in dentate gyrus (DG) of the hippocampus. In addition, there is a direct link between the reduction of neurons in the hippocampus and memory impairment. In this study, the effect of carnosic acid (CA) on the hippocampal neurogenesis was evaluated after 6-OHDA injury. Materials and Methods: Male Wistar rats were randomly divided into six groups. First group was injected by bilateral intra-nigral of 6-OHDA at a dose of 6μg (injury). Groups 2-5 were injured rats which received orally Rosemary extract containing 40% CA at doses of 25, 50 and100 mg/kg (treated) and distilled water (control), once daily in a period of 14 days before and after injury. The sixth group (sham) was injected with saline instead of neurotoxin. After treatment, the brains were removed and fixed with 4% paraformaldehyde, dehydrated, embedded in paraffin and cut into 10μm thick slices. Sections were stained with cresyl fast violet and cell counting of hippocampal regions was done.The loss of dopaminergic neurons in the 6-hydroxydopamine-lesioned rats, compared to sham-operated rats, was verified by tyrosine hydroxylase immunohistochemistry. Results: Immunostaining analysis revealed a high density of TH+ cells in sham compared to injured group. The number of DG granular and CA1 pyramidal cells were decreased significantly in both control and injured groups compared to sham (P<0.05). The number of granular and CA1pyramidal cells were increased significantly in CA (25, 50,100) and CA (50,100) treated groups respectively, compared to control and injured rats (P<0.05). The number of CA3 pyramidal cells was not increased significantly in treated groups compared to control and injured rats. Conclusion: CA plays an important role in protecting hippocampal neurons from further damage in response to 6-OHDA. Then it is the effective herbal drug with treatment potential to improve memory impairment in PD which caused by neurons degeneration in the hippocampus.
This study examines the role of marketing mangers' commitment and involvement in implementing marketing strategies. The data were collected from marketing managers of different organizations who had implemented a strategic marketing plan in the last five years. The study reveals that marketing mangers' commitment towards strategy implementation has a significant positive impact on organizational performance. Innovative culture, top management support and job autonomy were considered to be the key antecedents of managers' commitment. All three antecedents were found to have significant positive impact on commitment. In addition, commitment was found to partially mediate the links of top management support and autonomy with organizational performance. It was also found that marketing managers' involvement moderates the relationship between job autonomy and managers' commitment. The managerial implications are discussed.
. Prophylactic treatment with antiepileptic drugs (AEDs) has been recommended to prevent early seizure onset in patients with traumatic brain injury (TBI). However, the potential neuroprotective and/or detrimental effects of prophylactic AED treatment on behavioral and cognitive function after TBI are not well studied.
. To investigate the effects of a novel AED, levitiracetam (LEV), on behavioral and cognitive function after experimental TBI in rats.
. Adult male rats were administered LEV (intraperitoneal 50 mg/kg) or vehicle (saline; SL) daily for 20 days beginning 1 day after controlled cortical impact (CCI; 2.8 mm; 4 m/s) or sham surgery. Beam performance (days 1-6), Y-maze (day 7), and Morris water maze (days 14-19) postinjury testing was assessed.
. Daily LEV treatment improved motor function, increased novel arm exploration in the Y-maze, elicited greater hippocampal cell sparing, and decreased contusion volumes compared with CCI/SL rats. Daily LEV administration also reversed a TBI-induced decrease in regional glutamate transporter expression and neuroplastic marker proteins present 20 days post-CCI. Also, daily LEV treatment decreased regional IL-1β expression after TBI.
. These results suggest that daily LEV treatment has beneficial effects on histological, molecular, and behavioral elements of neurological recovery after TBI, in part, via modulation of neuroinflammatory and excitatory pathways.
Hyperactivation of glutamatergic N-methyl-D-aspartate (NMDA) receptors has been implicated in the excitotoxicity and pathophysiology of Parkinson's disease (PD). NMDA receptor blockers have been used clinically to treat dementia, but their efficacy is controversial. Modulation of NMDA receptors might improve neuroinflammation and cognitive deficits in PD. D-cycloserine (DCS), a partial agonist binding to the glycine binding site of NMDA receptors, has been demonstrated to improve cognitive function in primates and rodents. Our previous study showed that DCS can reduce motor, emotional, and cognitive dysfunctions, as well as neuroinflammation and neurodegeneration in a PD animal model and may therefore have potential for the treatment of neuroinflammation and cognitive dysfunction in patients with PD. In addition, increased expression of cyclooxygenase type-2 (COX-2) has been observed in dopaminergic neurons and activated microglia in the brain of both PD patients and PD animal models. COX-2 inhibitors can suppress activation of microglia and protect dopaminergic neurons from degeneration. Thus, a combination of DCS and COX-2 inhibitors might prove useful in suppressing neuroinflammation and cognitive deficits in PD.
The beneficial effects of growth hormone (GH) on memory and learning have previously been confirmed in both humans and in animal models. An important role of GABA(B) receptors for multiple forms of learning and memory has also been reported. In this study, we examined the effect of GH on the density and functionality of the metabotropic GABA(B) receptors in the rat brain. Male Sprague-Dawley rats (n = 24) divided into 3 groups were injected twice daily with recombinant human GH (0.07 or 0.7 IU/kg) for 7 days. The effects of the hormone were determined by quantitative autoradiography and by GABA(B) stimulated [(35)S]-GTPγS binding using the selective GABA(B) receptor agonist baclofen. The results demonstrate moderate but significant alterations in both receptor density and functionality in a number of brain regions. For example, a dose-dependent upregulation of GABA(B) receptors was found in the cingulate cortex, primary motor cortex and caudate putamen, whereas attenuation in the receptor density was encountered in, for example, the medial geniculate nucleus. Although the GH-induced effects on the GABA(B) receptor in brain areas associated with cognition were fairly pronounced, they were significant and we propose that the physiological responses observed after GH administration at least partly can be mediated through a mechanism involving GABA(B) receptors.
Lewy body disorders are a heterogenous group of neurodegenerative diseases, the morphological hallmark of which are Lewy bodies,
neuronal intracytoplasmic aggregations containing misfolded fibrillar α‐synuclein (AS) and a variety of other chemical substances.
Lewy bodies, regardless of their location (cortical or subcortical) and the phenotype of proteinopathies (amyloidopathy, synucleinopathy,
tauopathy) in which they occur, have a rather uniform biochemical and immunohistochemical profile, but may show some molecular
biological and developmental diversities. Current knowledge about the molecular basis of their principal constituent, AS,
a small presynaptic, natively unfolded protein that undergoes multiple conformational and translational modifications during
Lewy body formation as well as the major biochemical components of these inclusions are reviewed. However, the ultimate causes
and molecular pathways of their formation and the relevant role of AS with regard to neurotoxicity and neuroprotection and
its final role in dysfunction and death of involved neurons are to be clarified. Although Lewy bodies and AS‐positive dystrophic
(Lewy) neurites are present in a large number of human diseases as well as in the aged brain, the major disorders hallmarked
by these AS‐positive inclusions are sporadic Parkinson disease (brainstem type of Lewy body disease) with and without dementia
and different subtypes (phenotypes) of dementia with Lewy bodies. The essential clinical, neuropathological, and biochemical
data of these disorders and their nosological relations are critically reviewed. Their pathological diagnosis is established
by validated consensus criteria based on semiquantitative assessment of cortical and subcortical Lewy bodies as their common
hallmarks, and they are accompanied by multisystem degeneration with neuronal loss, gliosis, and complex biochemical deficiencies
with and without Alzheimer pathologies, the clinical impact of which is still under discussion. Considerable overlap between
both these two most frequent forms of α‐synucleinopathies and co‐occurrence of AS, amyloid β‐peptide, and tau deposits in
various neurodegenerative and aging disorders suggest collision of several proteinopathies with cross‐seeding and synergistic
interactions, confirmed by experimental and in vitro studies. Finally, the relations between the different proteinopathies
with respect to their pathogenesis are discussed, but their pathobiological relations are still to be elucidated. Despite
a wealth of experimental data, there is still no consensus on whether oligomers, protofibrils, or mature fibrils (or some
combination of these) of various proteins are the important toxic species that mediate neurodegeneration, nor do we understand
the mechanisms by which they compromise the function and viability of selective vulnerable cells.
The two most common neurological disorders of the basal ganglia are Parkinson's disease (PD) and Huntington's disease (HD). The most overt symptoms of these diseases are motoric, reflecting the loss of the striatal medium spiny neurons in HD and ascending substantia nigra dopaminergic cells in PD. However, both disease processes induce insidious psychiatric and cognitive syndromes that can manifest well in advance of the onset of motor deficits. These early deficits provide an opportunity for prophylactic therapeutic intervention in order to retard disease progression from the earliest possible point. In order to exploit this opportunity, animal models of HD and PD are being probed for the specific cognitive deficits represented in the disease states. At the neuronal level, these deficits are typically, but not exclusively, mediated by disruption of parallel corticostriatal loops that integrate motor information with sensory and higher order, "executive" cognitive functions. Dysfunction in these systems can be probed with sensitive behavioural tests that selectively probe these cognitive functions in mouse models with focal lesions of striatal or cortical regions, or of specific neurotransmitter systems. Typically these tests were designed and validated in rats. With the advent of genetically modified mouse models of disease, validated tests provide an opportunity to screen mouse models of disease for early onset cognitive deficits. This review seeks to draw together the literature on cognitive deficits in HD and PD, to determine the extent to which these deficits are represented in the current animal models of disease, and to evaluate the viability of selecting cognitive deficits as potential therapeutic targets. This article is part of a Special Issue entitled 'Animal Models'.
This study investigated the respective roles of the hippocampus, the amygdala, and the dorsal striatum in learning and memory. A standard set of experimental conditions for studying the effects of lesions to the three brain areas using an 8-arm radial maze was used: a win-shift version, a conditioned cue preference (CCP) version, and a win-stay version. Damage to the hippocampal system impaired acquisition of the win-shift task but not the CCP or win-stay tasks. Damage to the lateral amygdala impaired acquisition of the CCP task but not the win-shift or win-stay tasks. Damage to the dorsal striatum impaired acquisition of the win-stay task but not the win-shift or CCP tasks. These results are consistent with the hypothesis that the mammalian brain may be capable of acquiring different kinds of information with different, more-or-less independent neural systems. A neural system that includes the hippocampus may acquire information about the relationships among stimuli and events. A neural system that includes the amygdala may mediate the rapid acquisition of behaviors based on biologically significant events with affective properties. A neural system that includes the dorsal striatum may mediate the formation of reinforced stimulus-response associations.
It is proposed that the hippocampal formation makes a unique contribution to memory by providing the neural basis for the initial acquisition and storage of configural associations among events. A distinction is made between two kinds of memory processes: a simple associative process, which does not depend on the hippocampal formation, and a configural associative process, which does. The simple associative system records the organism’s experiences as changes in the strength of associations between elementary stimulus events. The configural associative system combines the representations of elementary stimulus events to construct unique representations and allows for the formation of associations between these configural representations and other elementary representations. In the present paper, the results of two experiments designed to test predictions of our theory are described. We then illustrate how the theory can be applied to explain a wide range of impairments that have been observed when learning and memory tasks have been employed to assess the effect of hippocampal formation damage. These include tasks that measure place learning, recognition memory, latent inhibition, serial-compound conditioning, discrimination-reversal learning, and stimulus-selection processes. The relationship of our position to some other views of hippocampal function is discussed, and we conclude with suggestions for future research.
The present study examined the effect of lesions of the caudate nucleus or fimbria-fornix on the acquisition of two water maze tasks. In both tasks, two rubber balls with different visual patterns were used as platforms (i.e., cues). The "correct" cue was attached to a submerged rectangular platform and could be mounted by an animal to escape the water. The "incorrect" cue was attached to a thin round pedestal and could not be mounted. In a spatial version of the task, the correct cue was located in the same quadrant of the maze on all trials, whereas the visual pattern on the cue was varied from trial to trial. Lesions of the fornix, but not the caudate nucleus, impaired acquisition of this spatial task in relation to control animals. In a simultaneous visual discrimination version of the task, the correct cue on all trials was one with a specific visual pattern, and the spatial location of the correct cue was varied from trial to trial. Lesions of the caudate nucleus, but not the fornix, impaired acquisition of this visual discrimination task in relation to control animals. The double dissociation observed supports the hypothesis that the hippocampus and caudate nucleus are parts of systems that differ in the type of memory they mediate.
The effect of posttraining intracerebral injections of the indirect dopamine (DA) agonist d-amphetamine, the direct D2 agonist LY 171555, and the direct D1 agonist SKF-38393 on the acquisition of two 8-arm radial maze tasks were examined. On a win-stay task, a light cue signaled the location of food in 4 randomly selected maze arms on each trial, and animals were required to visit each of the lit arms twice within a trial. Posttraining intracaudate injection of d-amphetamine (10.0 and 15.0 micrograms), LY 171555 (2.0 micrograms), and SKF-38393 (5.0 micrograms) all improved win-stay acquisition in relation to saline-injected controls. In contrast, posttraining intrahippocampal injection of DA agonists had no effect on win-stay acquisition. On a win-shift task, rats were allowed to obtain food from 4 randomly selected maze arms, followed by a delay period in which they were removed from the maze. They were returned to the maze for a retention test in which only those arms that had not been visited before the delay contained food. Posttraining intrahippocampal (but not intracaudate) injection of d-amphetamine (5.0 micrograms), LY 171555 (2.0 micrograms), and SKF-38393 (5.0 micrograms) all improved win-shift retention in relation to saline-injected controls. The results demonstrate a double dissociation of hippocampus and caudate nucleus memory functions and show that posttraining injection of both D1 and D2 agonists modulate the memory processes subserved by both hippocampus and caudate nucleus.
The traditional concept of memory disorder is deficiency of the long-term (LTM) but not short-term (STM) component of memory. STM impairment with LTM sparing is seldom reported. The present study investigated STM and LTM for nonverbal material in three neurological conditions associated with memory impairment: bilateral medial temporal lobe lesions (patient H.M.), Parkinson's disease (PD) and Alzheimer's disease (AD). Subjects received 3 tests of nonverbal memory: forward block span, immediate and delayed recall of the Wechsler Memory Scale drawings, and immediate and delayed recognition of abstract designs. Compared with the normal control group, the patient groups displayed different patterns of sparing and loss of the two components of memory: in PD, only STM was impaired; in medial temporal lobe amnesia, only LTM was impaired; and in AD, STM and LTM were both impaired. The contrasting patterns of sparing and loss of STM and LTM in PD and global amnesia were present for both recognition and recall. These results provide evidence that STM and LTM are dissociable processes and are served by separate neurological systems: STM depends upon intact corticostriatal systems, whereas LTM depends upon intact medial temporal lobe systems.
Place learning and memory were assessed in rats with selective damage to the fornix/fimbria or to subcortical structures which have a major connection with the hippocampal formation via the fornix/fimbria. Navigation to a hidden or visible platform in a fixed location was studied in the Morris water task in rats who were preoperatively trained in the task or who were preoperatively naive. All rats learned to navigate accurately to a visible platform. Only complete transection of the fornix/fimbria abolished both acquisition and retention of navigation to a hidden platform. Severe impairment of postoperative acquisition was produced by bilateral damage to the medial nucleus accumbens or bilateral damage to the anterior thalamic area. Nucleus accumbens or anterior thalamic damage produced little effect on retention of preoperatively acquired place navigation. Damage to medial septum or mammillary complex produced modest impairments evident only in postoperative acquisition.
The present experiments were designed to examine the hypothesis that the mammalian brain contains anatomically distinct memory systems. Rats with bilateral lesions of caudate nucleus or fimbria-fornix and a control group were tested postoperatively on 1 of 2 versions of the radial maze task. In a standard win-shift version, each of the 8 arms of the maze was baited once, and the number of errors (revisits) in the first 8 choices of each trial was recorded. Fimbria-fornix rats were impaired in choice accuracy, while caudate animals were unimpaired relative to controls. Different groups of rats with similar lesions were tested on a newly developed win-stay version of the radial maze, in which the location of 4 randomly selected baited arms was signaled by a light at the entrance to each arm, and which required rats to revisit arms in which reinforcement had been previously acquired within a trial. Rats with fimbria-fornix lesions were superior to controls in choice accuracy on the win-stay radial maze task, while caudate animals were impaired relative to controls. The results demonstrate a double dissociation of the mnemonic functions of the hippocampus and caudate nucleus. Some implications of the presence of 2 memory systems in the mammalian brain are discussed.
Separate groups of rats with lesions in the parietal cortex (PC) or hippocampal formation (HF) were tested for acquisition and retention of the Morris water maze cognitive mapping task. Some of the animals in each lesion group received preoperative training in the task. Other animals in each group received no preoperative training. The results indicate that although both lesions lead to a cognitive mapping impairment in both the acquisition and retention of the task, the animals with PC lesions were more severely impaired than were the animals with HF lesions, as indicated by quantitative measures. However, qualitative aspects of the animals' swim behavior indicate that the HF damaged animals tend to use "nonmapping" strategies to solve the tasks, which suggests that the qualitative nature of their impairment differs from that of the PC damaged animals. The results of this study support the hypothesis that PC plays an important role in the processing of information about space that is allocentric or external to the body.
Electrophysiological studies have shown that single cells in the
hippocampus respond during spatial learning and
exploration1-4, some firing only when animals enter specific
and restricted areas of a familiar environment. Deficits in spatial
learning and memory are found after lesions of the hippocampus and its
extrinsic fibre connections5,6 following damage to the medial
septal nucleus which successfully disrupts the hippocampal theta
rhythm7, and in senescent rats which also show a correlated
reduction in synaptic enhancement on the perforant path input to the
hippocampus8. We now report, using a novel behavioural
procedure requiring search for a hidden goal, that, in addition to a
spatial discrimination impairment, total hippocampal lesions also cause
a profound and lasting placenavigational impairment that can be
dissociated from correlated motor, motivational and reinforcement
aspects of the procedure.
Involvement of the hippocampus and caudate nucleus in place and response learning was examined by functionally inactivating these brain regions bilaterally with infusions of lidocaine. Rats were trained to approach a consistently baited arm in a cross-maze from the same start box (four trials/day/14 total days). On Days 8 and 16 a single probe trial was given, in which rats were placed in the start box opposite that used in training and allowed to approach a maze arm. Three minutes prior to the probe trial, rats received bilateral injections of either saline or a 2% lidocaine solution (in order to produce neural inactivation) into either the dorsal hippocampus or dorsolateral caudate nucleus. On the probe trials, rats which entered the baited maze arm (i.e., approached the place where food was located during training) were designated place learners, and rats which entered the unbaited maze arm (i.e., made the same turning response as during training) were designated response learners. Saline-treated rats displayed place learning on the Day 8 probe trial and response learning on the Day 16 probe trial, indicating that with extended training there is a shift in learning mechanisms controlling behavior. Rats given lidocaine injections into the hippocampus showed no preference for place or response learning on the Day 8 probe trial, but displayed response learning on the Day 16 probe trial, indicating a blockade of place learning following inactivation of the hippocampus. Rats given lidocaine injections into the caudate nucleus displayed place learning on both the Day 8 and the Day 16 probe trials, indicating a blockade of response learning following inactivation of the caudate nucleus. The findings indicate: (1) the hippocampus and caudate nucleus selectively mediate expression of place and response learning, respectively (2), in a visually cued extramaze environment, hippocampal-dependent place learning is acquired faster than caudate-dependent response learning, and (3) when animals shift to caudate-dependent response learning with extended training, the hippocampal-based place representation remains intact.
Amnesic patients and nondemented patients with Parkinson's disease were given a probabilistic classification task in which
they learned which of two outcomes would occur on each trial, given the particular combination of cues that appeared. Amnesic
patients exhibited normal learning of the task but had severely impaired declarative memory for the training episode. In contrast,
patients with Parkinson's disease failed to learn the probabilistic classification task, despite having intact memory for
the training episode. This double dissociation shows that the limbic-diencephalic regions damaged in amnesia and the neostriatum
damaged in Parkinson's disease support separate and parallel learning systems. In humans, the neostriatum (caudate nucleus
and putamen) is essential for the gradual, incremental learning of associations that is characteristic of habit learning.
The neostriatum is important not just for motor behavior and motor learning but also for acquiring nonmotor dispositions and
tendencies that depend on new associations.
Content and contextual memory for remote public figures and events was assessed with a modified version of the Presidents Test in patients with Alzheimer's disease (AD) or Parkinson's disease (PD). Contributions of executive functioning, semantic memory, and explicit anterograde memory to remote memory abilities were also examined. The AD group had temporally extensive deficits in content and contextual remote memory not accountable for by dementia severity. The PD group did not differ from the control group in remote memory, despite anterograde memory impairment. These results support the position that different component processes characterize remote memory, various mnemonic and nonmnemonic cognitive processes contribute to remote memory performance, and anterograde and remote memory processes are dissociable and differentially disrupted by neurodegenerative disease.
Considerable evidence shows that post-training administration of dopamine agonists can enhance memory through actions on consolidation processes, but relatively little is known regarding the effects of dopamine antagonists on consolidation. These experiments investigated the effects of post-training systemic administration of the D2 receptor antagonist sulpiride on consolidation of memory for two versions of the Morris water maze task. Rats trained in either the hidden (spatial) or visible (cued) platform version received a subcutaneous injection of sulpiride or vehicle immediately following training. Retention testing 48 hr later revealed that relative to vehicle controls, sulpiride reduced platform latencies in both task versions, suggesting that like dopamine agonists, sulpiride can also have memory-enhancing effects.
The objective of the present investigation was to test the effects of benserazide/L-dopa treatment in a model of learning and memory deficits associated with early Parkinson's disease. Intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused a lesion in the substantia nigra, compact part and a specific loss of dopamine (DA) and its metabolites in the striatum of rats and a memory impairment in the two-way active avoidance task. The administration of benserazide/L-dopa (50 and 200 mg/kg) to the MPTP-lesioned rats restored the striatal level of DA, but did not reverse the MPTP-induced learning and memory impairment. As this treatment caused a large increase of DA levels in extrastriatal brain regions of the MPTP-lesioned animals, this study suggests that benserazide/L-dopa therapy was not effective in improving the observed learning impairment because this treatment appears to tilt the balance between DA levels in the striatum and in the extrastriatal regions, such as frontal cortex and limbic structures, resulting in a cognitive deficit.
Each 15 patients with damage to the prefrontal cortex, the medial temporal lobe, or with Parkinson's disease were compared with each other and with two groups of education and age-matched, non-brain damaged control patients on a number of cognitive tests, with emphasis on measuring explicit and implicit memory functions. The tests covered intelligence, attention and concentration, executive functions, temporo-spatial memory, priming, procedural, episodic, and meta-memory. The results obtained deviate in a number of ways from assumptions frequently made. While medial temporal lobe damaged patients performed - as expected - poorest in all explicit memory tests, Parkinson patients, in the initial phase of illness manifestation, already had major amnestic problems. Some deficits were even seen in priming tests. Deficits in Parkinson patients may be enhanced by overly cautious reaction tendencies. Prefrontally damaged patients performed quite normal in a number of tests, however, they displayed problems in attention-related functions. Our results point to substantial differences in the cognitive behavior of prefrontals and Parkinson's and demonstrate that unilateral damage of medial temporal lobe structures may already have severe effects on memory. Furthermore, age can significantly influence cognitive performance, especially in combination with brain pathology.
Two behavioral testing procedures, a spatial discrimination and a cued discrimination, were used in a water maze to assess memory enhancement following posttraining administration of
d-amphetamine, an indirect catecholamine agonist, and quinpirole, a dopaminergic D2 receptor agonist. Ss were 134 male rats. On a retention test session 24 hrs later, latency to mount the escape platform was used as a measure of memory. In both tasks, the retention test escape latencies of Ss given
d-amphetamine or quinpirole were lower than those of saline-injected controls. Control experiments indicated that the effects of
d-amphetamine on retention were due to an influence on memory for the type of discrimination learned (i.e., spatial or cued). Findings suggest a neuromodulatory role for dopaminergic systems in both tasks. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
There are several dopaminergic pathways present in mammalian brain (Ungerstedt, 1971a, b, c, d; Schultz, 1982). Perhaps the
most studied of these is the nigrostriatal pathway, which arises from pigmented cell bodies in the zona compacta of the substantia
nigra and projects rostrally to the neostriatum (corpus striaturn). Parkinson’s disease is a syndrome of diverse etiology
that is characterized by a degeneration of the above-mentioned nigrostriatal pathway. It has been estimated that the incidence
of parkinsonism in the general population ranges from 100 to 150 cases per 100,000, with the prevalence being considerably
greater in an older population sample (Schoenberg, 1987; Yahr, 1977). Biochemical and pathological characteristics of this
disease include a greatly diminished neostriatal content of dopamine (DA) and its major metabolites and a marked loss of nerve
cells in the zona compacta of the substantia nigra. Additional neuronal systems involved include noradrenergic and cholinergic
systems.
Parkinson's disease (PD) symptoms originate from the loss of the dopaminergic control of neuronal activity in the striatum. Permanent loss of dopaminergic terminals in the striatum results in an abnormal activity of striatal neurons. The therapeutic treatment with exogenous dopamine, therefore, temporarily restores a balanced synaptic excitation of striatal neurons, counteracting pre- and postsynaptically the excessive glutamate release caused by the degeneration of nigrostriatal dopaminergic fibers. However, chronic treatment is associated with adverse effects that might reflect nonphysiological dopamine replacement. Basic studies on experimental animal models of PD are of crucial importance for the development of therapeutic agents able to provide relief to individuals with PD, without the adverse effects associated with currently available drugs.
Changes in stereotyped sniffing, biting and hyperactivity induced by apomorphine and d-amphetamine in the rat were determined after bilateral 6-hydroxydopamine (6-OHDA) lesions (8–16 μg/4 μl) of the extrapyramidal caudate-putamen (CP) (anterior and centre), globus pallidus (GP) and substantia nigra (SN), the mesolimbic nucleus accumbens (ACB), tuberculum olfactorium (TUO) and central amygdaloid nucleus (ACE). Lesions were also induced in the medial forebrain bundle in the lateral hypothalamus (LH).
Rats with damage to the fimbria-fornix were tested for the post-operative retention of a preoperatively learned discrimination on a radial arm maze. The maze contained two sets of arms. One set, which never had food on them, comprised the “reference memory” task. The correct response on every approach to each arm in this unbaited set was to refrain from entering it. A second set of arms, each of which had one pellet of food on it at the beginning of a test, comprised the “working memory” task. The correct response to each of the arms in this baited set changed during a test. On the first approach to each of them, the correct response was to run down the arm and obtain the food there; on all subsequent approaches the correct response was to refrain from running down the arm because the food was no longer available. At the end of postoperative testing, performance on the reference memory task was normal, while performance on the working memory task was severely impaired by large lesions and slightly impaired by small ones. Rats with the most complete fimbria-fornix lesions showed no signs of improvement in working memory. This behavioural dissociation suggests a differential involvement of the hippocampus in working memory as compared to reference memory.RésuméOn a testé des rats avec lésion de la fimbria et du fornix sur la rétention post-opératoire d'une discrimination de labyrinthe à branches radiales apprise pré-opératoirement. Le labyrinthe comportait 2 séries de branches. Une série sur laquelle on ne mettait jamais de nourriture représentait une épreuve de “mémoire de référence”. La réponse correcte dans cette série pour toute approche à chaque branche était de ne pas y pénétrer. Une second série de branches dont chacune avait au début du test un morceau de nourriture représentait la tâche de “mémoire de travail”. La réponse correcte à chacune des branches dans cette série changeait au cours du test. A la premiére approche de chacune des branches, la réponse correcte était de parcourir toute la branche pour obtenir la nourriture. A toutes les approches suivantes, la réponse correcte était de ne pas y pénétrer puisqu'il n'y avait plus de nourriture. A la fin du test post-opératoire, les performances sur la tâche de “mémoire de référence” étaient normales tandis que les performences sur la tâche de “mémoire de travail” étaient gravement perturbées par les grandes lésions et légèrement perturbées par les petites lésions. Chez les rats avec lésions fimbria-fornix les plus complétes, on ne constatait aucun signe d'amélioration dans la “mémoire de travail”. Ces dissociations comportementales suggèrent une implication différente de l'hippocampe dans la “mémoire de travail” et dans la “mémoire de référence”.ZusammenfassungRatten mit Schädigung der Fimbriae des Fornix wurden auf das postoperative Gedächtnis für ein präoperativ erlerntes Diskriminationsmuster getestet. Es muβte die räumliche Verteilung eines strahlenförmigen Irrgartens behalten werden. Der Irrgarten setzte sich aus zwei Arten von Gängen zusammen. Einer davon enthielt niemals Futter, er wurde als Test für ein “reference”-Gedächtnis angesehen. Das richtige Verhalten bei jedem Versuch bestand darin, in diesem nicht mit Futter versehenen Bereich nicht einzutreten. Eine zweite Anordnung von Gängen, die jeweils bei Testbeginn Futter enthielt, wurde als “working”-Gedächtnis betrachtet. Das korrekte Verhalten in jedem dieser Gänge in diesem Bereich wechselte während des Testversuchs. Beim ersten Versuch bestand die korrekte Antwort darin, in den Gang zu laufen, in dem sich das Futter befand. In allen nachfolgenden Versuchen war es korrekt, nicht dorthin zu laufen, weil nun das Futter nicht mehr zur Verfügung stand. Bei Ende der Untersuchung, nach Durchführung der Operation, erwies sich, daβ das “reference”-Gedächtnis unbeeinträchtigt geblieben war, während das “working”-Gedächtnis bei ausgedehnten Läsionen stark gelitten hatte, bei leichteren Schäden geringer. Dieses unterschiedliche Verhalten spricht dafür, daβ der Hippocampus in verschiedener Weise in die Gedächtnisfunktionen einbezogen ist.
Groups of Long-Evans rats with bilateral lesions of the caudate nucleus, sham lesions, or no lesions were given one trial per day in an eight-arm radial maze. The same four maze arms were baited on each trial. The remaining four arms never contained food. Optimal performance required animals to enter each of the baited arms only once on each trial and to avoid entering the arms in the unbaited set. Rats with caudate lesions learned to enter each of the baited arms only once on each trial. However, these rats were severely impaired in learning to avoid entering the arms in the unbaited set. Implications for dual-memory theories are discussed.
The discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans and other primates by selective destruction of substantia nigra dopaminergic neurons has spurred research to define the mechanisms underlying its toxicity. To avoid variables such as tissue distribution, extracerebral metabolism and blood-brain barrier permeability, the authors studied the neurochemical and morphologic effects of direct perinigral infusions of various concentrations of MPTP, its metabolites and analogs in the rat. MPTP, in the highest dose used, 1000 nmol, decreased dopamine and its metabolites in ipsilateral striatum by approximately 75%, whereas 3,3-dimethyl-MPTP (which is oxidized to 1,3,3-trimethyl-4-phenyl-2,3-dihydropyridinium cation but not to a pyridinium species) had no effect. The 2,2 and 3,3-dimethyl analogs of 1-methyl-4-phenyl-2,3-dihydropyridinium cation which also cannot be oxidized to pyridinium species, reduced striatal dopamine, suggesting that these compounds are toxic in their own right. 1-Methyl-4-phenylpyridinium cation (MPP+) and its 4-(4-fluorophenyl) and 4-(2-pyridyl) analogs that have less negative reduction potentials than MPP+, were most potent in decreasing striatal dopamine and metabolites, with MPP+ being 5 to 10 times more effective than its two analogs and approximately 100 times more potent than MPTP and the two dimethyl 1-methyl-4-phenyl-2,3-dihydropyridinium cation analogs. These findings suggest that MPP+ is ultimately responsible for MPTP toxicity but does not act via oxidant stress mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
The ability of intrahippocampal grafts of fetal septal-diagonal band tissue, rich in developing cholinergic neurons, to ameliorate cognitive impairments induced by bilateral fimbria-fornix transections in rats was examined in three experiments using the Morris water-maze to test different aspects of spatial memory. Experiment 1. Rats with fimbriafornix lesions received either septal cell suspension grafts or solid septal grafts; normal rats and rats with lesions alone were used as controls. Sixteen weeks after surgery, the rats' spatial learning and memory were tested in the water-maze using a place test, designed to investigate place navigation performance, in which rats learned to escape from the water by swimming to a platform hidden beneath the water's surface. After 5 days of training, the rats were given a spatial probe test in which the platform was removed from the tank to test spatial reference memory. Experiment 2. The same rats used in Exp. 1 were tested in a delayed-match-to-sample, working memory version of the water-maze task. The platform was located in one of two possible locations during each trial, which was composed of 2 swims. If the rat remembered the location of the platform on the 2nd swim of a trial, it should find the platform more quickly on that swim, and thereby demonstrate working memory. Experiment 3. Prior to receiving fimbria-fornix lesions, normal rats were trained in a modification of the water-maze task using alternating cue navigation and place navigation trials (i.e., with visible or non-visible escape platforms). The retention and reacquisition of the place task and the spatial probe test were examined in repeated tests up to 6 months after the lesion and intrahippocampal grafting of septal cell suspensions. The effects of central muscarinic cholinergic receptor blockade with atropine were also tested. Normal rats performed well in both the place and spatial probe tests. In contrast, rats with fimbria-fornix lesions only were unable to acquire or retain spatial information in any test. Instead, these rats adopted a random, non-spatial search strategy, whereby their latencies to find the platform decreased in the place navigation tasks. Sixty to 80% of the rats with septal suspension or solid grafts had recovered place navigation, i.e., the ability to locate the platform site in the tank, in Exp. 1 and 3, and they showed a significantly improved performance in the working memory test in Exp. 2. Atropine abolished the recovered place navigation in the grafted rats, whereas normal rats were impaired to a lesser extent.(ABSTRACT TRUNCATED AT 400 WORDS)
A series of experiments examined the proposal that the primary effect of hippocampal damage in rats is to disrupt working memory. Although extensive hippocampal lesions produced a severe impairment in forced-choice alternation--a test of spatial working memory--the same lesions did not impair the acquisition of a non-spatial test of working memory--delayed non-matching-to-sample. This test of object recognition required the rats to select that arm in a Y-maze which contained unfamiliar stimuli. Rats with hippocampal lesions were able to learn and perform this task at normal rates, even with retention delays of as long as 60 s. Two additional experiments helped confirm that the animals had indeed learnt a non-spatial test of working memory. The final experiment examined whether hippocampal lesions resulted in an increased sensitivity to proactive interference. It was found that repetition of test stimuli within a session, which increased interference, did attenuate recognition performance but there was no evidence that the animals with hippocampal lesions were differentially affected.
A simple and rapid dissection procedure was adopted to sample representative areas of the main meso-telencephalic dopaminergic (DA) neuron systems (nigrostriatal and meso-limbic-cortical) in the rat CNS. The object was to explore nerve terminal fields, cell body groups and dendrites, and to investigate the DA utilization rates in these regions. DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) as well as noradrenaline (NA) were determined by liquid chromatography with electrochemical detection. Selective NA denervation with the neurotoxin DSP4 did not significantly change the DA levels in any of the regions studied, showing that the main part of the DA analysed originated from DA neurons. Administration of the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (H44/68) resulted in a time-dependent, often multi-phasic, DA and NA depletion pattern that varied between different regions. Comparison between the rate of DA decline and DOPAC/DA or HVA/DA ratios (also indices for DA utilization) in the various regions showed that the initial rate of DA disappearance after H44/68 appeared to be the most relevant index of DA utilization. The most rapid initial DA decline after H44/68 was found in the cortical regions (frontal, cingulate, and entorhinal) and the cell body areas A9 and A10, in particular in the cingulate cortex (t1/2 approximately equal to 20 min), indicating a very rapid DA turnover in this region. DA disappearance was clearly slower in striatum (t1/2 approximately equal to 45 min) and the slowest rates were found in the olfactory tubercle and the nucleus accumbens (t1/2 approximately equal to 1.5-2 h). The DA disappearance (t1/2 approximately equal to 45 min) pattern in the dendritic area (substantia nigra, pars reticulata) suggested an axon-terminal like behaviour of the DA dendrites with respect to DA utilization. In general, the DA metabolite/DA ratios obtained for the various regions agreed closely with these results. The rate of NA disappearance after H44/68 was slower than that of DA in most regions. The most rapid NA decline was found in the cortical regions (t1/2 approximately equal to 1-2 h), while very slow in the A9 and A10 regions (t1/2 approximately equal to 3-5 h).
This experiment examines the notion that in the rat the hippocampal formation is an essential structure in the neurological representation of spatial abilities. Spatial localization by rats with different types of hippocampal damage, including bilateral electrolytic lesions, unilateral and bilateral kainic acid-induced CA3-CA4 lesions, and unilateral and bilateral colchicine-induced dentate gyrus lesions, was compared with vehicle-injected and normal control groups in the Morris water task. The task required the rats to escape from cold water by finding a submerged and hidden platform located at a fixed place within the room. The start point was varied randomly from trial to trial and there were no local cues available to indicate the position of the hidden platform. After training, the platform was moved. Escape latencies and the initial swimming headings revealed that all lesion groups, except the unilateral CA3-damaged group, were impaired at finding the platform: the dentate-damaged rats exhibited the greatest deficit. When the platform was moved the control rats swam mainly in the part of the pool that had previously contained the platform and, on finding it in the new location, they showed a marked dishabituation of rearing. None of the bilateral lesion groups showed these effects.
This experiment investigated the ability of rats with dorsal striatal or fornix damage to learn the location of a visible platform in a water maze. We also assessed the animals' ability to find the platform when it was hidden (submerged). Rats with neurotoxic damage to the dorsal striatum acquired both the visible and hidden platform versions of the task, but when required to choose between the spatial location they had learned and the visible platform in a new location they swam first to the old spatial location. Rats with radio-frequency damage to the fornix acquired the visible platform version of the water maze task but failed to learn about the platform's location in space. When the visible platform was moved to a new location they swam directly to it. Normal rats acquired both the visible and hidden platform versions of the task. These findings suggest that in the absence of a functional neural system that includes dorsal striatum, spatial information predominantly controlled behavior even in the presence of a cue that the animals had previously been reinforced for approaching. In the absence of a functional hippocampal system behavior was not affected by spatial information and responding to local reinforced cues was enhanced. The results support the idea that different neural substrates in the mammalian nervous system acquire different types of information simultaneously and in parallel.
An overview of lesion experiments concerned with the involvement of the hippocampus in learning and memory in the rat is presented. Multiple injections of small amounts of ibotenic acid were used to selectively remove the hippocampus (dentate gyrus, hilar cells, CA1-CA3 pyramidal cells). Similar selective, axon-sparing ibotenate lesions of hippocampus were used in a series of learning and memory experiments employing tasks that are thought to be important in hippocampal function. The performance of rats with the hippocampus removed was compared with that of control animals in the acquisition and retention of spatial versus nonspatial information, forgetting of spatial and nonspatial information, contextual learning, recognition memory and concurrent discrimination learning, and complex representational learning (conditional discrimination and negative patterning learning). The general finding that rats without a hippocampus were impaired on those tasks that required the utilization of spatial and contextual information stands in contrast with the spared performance that was found in learning about and handling (even complex) nonspatial information. Rather than support for views that emphasize a role for the hippocampus in specific memory processes (working memory, declarative memory, temporary memory buffer, configural learning), the present results are more compatible with the idea that the hippocampus plays an especially important role in processing and remembering spatial and contextual information. The limited data that are available using more selective lesions of related hippocampal formation structures (entorhinal cortex, subiculum) suggest that these structures also make important contributions to learning and memory, and that some of these contributions may be different from those made by the hippocampus.
This study investigated the respective roles of the hippocampus, the amygdala, and the dorsal striatum in learning and memory. A standard set of experimental conditions for studying the effects of lesions to the three brain areas using an 8-arm radial maze was used: a win-shift version, a conditioned cue preference (CCP) version, and a win-stay version. Damage to the hippocampal system impaired acquisition of the win-shift task but not the CCP or win-stay tasks. Damage to the lateral amygdala impaired acquisition of the CCP task but not the win-shift or win-stay tasks. Damage to the dorsal striatum impaired acquisition of the win-stay task but not the win-shift or CCP tasks. These results are consistent with the hypothesis that the mammalian brain may be capable of acquiring different kinds of information with different, more-or-less independent neural systems. A neural system that includes the hippocampus may acquire information about the relationships among stimuli and events. A neural system that includes the amygdala may mediate the rapid acquisition of behaviors based on biologically significant events with affective properties. A neural system that includes the dorsal striatum may mediate the formation of reinforced stimulus-response associations.
• Objective.
—Comparing the pattern of spared and impaired memory functions in neurodegenerative diseases known to affect different brain structures.Design.
—Various situations of acquisition (free encoding or controlled encoding) and retrieval (immediate and delayed free and cued recall, recognition) were used.Setting.
—Referral center.Patients.
—Fifteen for each disease (ie, senile dementia of the Alzheimer type [SDAT], Parkinson's, and Huntington's), matched for education, severity of dementia, and depression.Main Outcome Measures.
—Comparison of free and controlled encoding situations, relationships between memory, executive, and linguistic functions test scores.Results.
—In the free encoding situation: no difference among the three groups, but higher numbers of intrusions and false recognitions in SDAT. In the controlled situation: cued recall and recognition scores significantly higher in Parkinson's disease and Huntington's disease than in SDAT. Memory performances correlated with executive functions test scores in Huntington's disease and Parkinson's disease, but not in SDAT. All results significant at P<.01.Conclusions.
—Clear distinction between the true amnesic syndrome of SDAT, compatible with lesions of hippocampus and temporal cortex, and the inefficient planning of memory processes of Huntington's disease and Parkinson's disease, which might result from a striatofrontal dysfunction.
The hippocampal formation has long been thought to play a role in learning and memory. Previous studies from our laboratory examined the organization of mesencephalic projections to the hippocampal formation in the rat. In order to evaluate the effects on learning and memory of retrograde selective lesions of mesencephalic dopaminergic neurons, following bilateral injection of 6-hydroxydopamine in the dorsal and ventral subiculum and adjacent CA1 field of the hippocampal formation, young adult Sprague-Dawley rats were trained in classical inhibitory avoidance, inhibitory avoidance using a multiple trial (training to criterion) and the standard Morris water maze task (cued and spatial versions). With regard to inhibitory avoidance, retention was examined one, three and 10 days after training. Concerning the Morris water maze task, 6-hydroxydopamine-lesioned and sham-operated rats received four training trials on each of four days. After training sessions, the rats were tested during a 60-s probe trial (free-swim trial) in which the platform was removed from the maze. The loss of mesencephalic dopaminergic neurons in the 6-hydroxydopamine-lesioned rats, compared to sham-operated rats, was verified by tyrosine hydroxylase immunohistochemistry. Although the 6-hydroxydopamine-lesioned rats were indistinguishable from sham-operated rats in performing the inhibitory avoidance and the cued version of the Morris water maze task, in the spatial version of the Morris water maze, lesioned rats, compared to controls, exhibited significant differences in the latency (P < 0.05), quadrant time (P < 0.01) and number of platform crossings (P < 0.05). These results suggest that the rat's ability to acquire spatial learning and memory for place navigation in the Morris water maze is likely to be dependent also on the integrity of mesohippocampal dopaminergic connections.
Neuropsychological investigations of patients with Parkinson's disease have shown specific impairments even in the early stages of the disease, which include deficit of behavioural regulation in sorting or planning tasks, defective use of memory stores, and impaired manipulation of internal representation of visuospatial stimuli. These deficits, reported in a disease which predominantly involves subcortical structures, have drawn attention to a potential role of the basal ganglia in cognitive processes. Given the modulatory role of the basal ganglia, these disorders might result from more fundamental deficits concerning the allocation of attentional resources, the temporal organization of behaviour, the maintenance of representations in working memory or the self-elaboration of internal strategies, all of which resemble dysfunctions of processes that are commonly considered to be controlled by the frontal lobes. This suggests a functional continuity or complementarity between the basal ganglia and association areas of the prefrontal cortex. The recent description in primates of segregated loops that interconnect discrete regions of the caudate nucleus to the dorsolateral and orbitofrontal regions of the prefrontal cortex via the thalamus may give some support to this hypothesis. Alternatively, degeneration of the ascending cholinergic and catecholaminergic neuronal systems may contribute, at least in part, to the occurrence of this frontal-lobe-like symptomatology associated with Parkinson's disease.
Intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) caused a lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats. The animals were then tested in the two-way active avoidance task. MPTP-treated animals presented lower learning scores in the training and test sessions, an effect that was not caused by motor impairment or by a decreased sensitivity to footshock since their reaction time to the footshock (unconditioned stimulus - UCS) was not reduced. These lower scores were also not attributable to lower acoustic sensitivity or to a slowing in the association of the sound cue (conditioned stimulus - CS) with the UCS since the reaction time to the CS in the active avoidance response did not differ between MPTP-treated and control groups. Therefore, these results are more properly attributable to an impairment of the memory acquisition and retention processes. In addition, this study is presented as a model of early Parkinson's Disease amnesia and is discussed in terms of the importance of the nigrostriatal pathway to memory acquisition and storage processes.
A theory of multiple parallel memory systems in the brain of the rat is described. Each system consists of a series of interconnected neural structures. The "central structures" of the three systems described are the hippocampus, the matrix compartment of the dorsal striatum (caudate-putamen), and the amygdala. Information, coded as neural signals, flows independently through each system. All systems have access to the same information from situations in which learning occurs, but each system is specialized to represent a different kind of relationship among the elements (stimulus events, responses, reinforcers) of the information that flows through it. The speed and accuracy with which a system forms a coherent representation of a learning situation depend on the correspondence between the specialization of the system and the relationship among the elements of the situation. The coherence of these stored representations determines the degree of control exerted by each system on behavior in the situation. Although they process information independently the systems interact in at least two ways: by simultaneous parallel influence on behavioral output and by directly influencing each other. These interactions can be cooperative (leading to similar behaviors) or competitive (leading to different behaviors). Experimental findings consistent with these ideas, mostly from experiments with rats, are reviewed.
A lesion in the substantia nigra pars compacta (SNc) of rats induced by intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused specific loss of dopamine and its nonconjugated metabolites in the dorsal striatum and in the prefrontal cortex (PFC), but not in the hippocampus or the ventral striatum (nucleus accumbens). This lesion did not alter the motor performance of the rats or learning of a spatial reference memory task in the water maze but impaired learning of a spatial working memory task and also of a cued version of the water maze. The results are discussed by relating the selective memory deficits observed in these water maze tasks to the PFC, dorsal striatum, and hippocampus. Some parallels between the memory deficits in these SNc-lesioned rats and Parkinson's disease patients are also discussed.
Levodopa treatment restores the striatal level of dopamine but fails to reverse memory deficits in rats treated with MPTP, an animal model of ParkinsonÕs disease
- M S Gevaerd
- E Miyoshi
- R Silveira
- N S Canteras
- R N Takahashi
- C Da Cunha
Gevaerd, M. S., Miyoshi, E., Silveira, R., Canteras, N. S., Takahashi,
R. N., & Da Cunha, C. (2001). Levodopa treatment restores the
striatal level of dopamine but fails to reverse memory deficits in rats
treated with MPTP, an animal model of ParkinsonÕs disease.
International Journal of Neuropsychopharmacology, 4, 361-370.
Impaired learning in a spatial working memory version and in a cued version of the water maze in rats with MPTP-induced mesencephalic dopaminergic lesions
- E Miyoshi
- S Wietzikoski
- M Camplessei
- R Silveira
- R N Takahashi
- C Da Cunha
Miyoshi, E., Wietzikoski, S., Camplessei, M., Silveira, R., Takahashi,
R. N., & Da Cunha, C. (2002). Impaired learning in a spatial
working memory version and in a cued version of the water maze in
rats with MPTP-induced mesencephalic dopaminergic lesions.
Brain Research Bulletin, 58, 41–47.
Electrophysiology of dopamine in normal and denervated striatal neurons
- P Calabresi
- D Centonze
- G Bernardi
Calabresi, P., Centonze, D., & Bernardi, G. (2000). Electrophysiology
of dopamine in normal and denervated striatal neurons. Trends in
Neursocience, 23(Suppl S), S57-S63.
Multiple rewards signals in the brain
- Shultz
Levodopa treatment restores the striatal level of dopamine but fails to reverse memory deficits in rats treated with MPTP, an animal model of Parkinson’s disease
- Gevaerd
Impaired learning in a spatial working memory version and in a cued version of the water maze in rats with MPTP-induced mesencephalic dopaminergic lesions
- Miyoshi
Electrophysiology of dopamine in normal and denervated striatal neurons
- Calabresi