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A schematic diagram of the connectivity within and between the mesostriatal pathways and related structures. Shown are the ipsilateral (solid lines) and contralateral (dashed lines) projections of fibers containing DA (blue), GABA (red), or glutamate (green). Abbreviations: PFC, Prefrontal Cortex; EC, Entorhinal cortex; Hipp, Hippocampus; LHb, Lateral Habenula; Str, Striatum; dStr, Dorsal Striatum; NAc, Nucleus Accumbens; GP, Globus pallidus; EP, Entopeduncular nucleus; VP, Ventral Pallidum; SNc, Substantia Nigra Pars Compacta; SNr, Substantia Nigra Pars Reticulata; VTA, Ventral Tegmental Area.
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The mesostriatal dopaminergic system, which comprises the mesolimbic and the nigrostriatal pathways, plays a major role in neural processing underlying motor and limbic functions. Multiple reports suggest that these processes are influenced by hemispheric differences in striatal dopamine (DA) levels, DA turnover and its receptor activity. Here, we...
Citations
... ДГ-деструкция не влияет на гиперлокомоцию, индуцированную амфетамином. Деструкция ВГ вызывает повышение спонтанной и индуцированной агонистами дофамина двигательной активности [42,43,44]. Поведенческие изменения, вызванные деструкцией ВГ, могут обнаруживаться примерно через 2 недели после операции [45]. ...
Animal modeling of schizophrenia is essential for understanding the neurobiological basis of the disease, as well as for the development of new antipsychotic drugs with improved therapeutic efficacy and safety profile. The review aims at summarizing the methodology and practical aspects of schizophrenia modeling based on dysontogenetic disturbances of the central nervous system in rats and mice. Environmental factors or the destruction of brain structures during prenatal or postnatal periods of development cause reorganization of neural networks, leading to irreversible changes in the function of the central nervous system, which usually appear after puberty. Developmental and lesion models of schizophrenia are widely regarded as the most appropriate due to their ability to reproduce characteristic behavioral and cognitive impairments with a delayed onset of symptoms, which is consistent with the clinical presentation of schizophrenia in humans.
... The current study uses a unilateral EDiPs model, thus it is important to consider the possibility of confounds from contra-lateral projections of DA neurons. In rodents DA fibres from the substantia nigra pars compacta, the ventral tegmental area (VTA) and posterior hypothalamic area have only 1-3% contralateral projections into the DS 23 . Thus, we consider the contribution of afferents from the contralateral EDiPs substantia nigra would be minimal. ...
One of the most robust neurochemical abnormalities reported in patients with schizophrenia is an increase in dopamine (DA) synthesis and release, restricted to the dorsal striatum (DS). This hyper functionality is strongly associated with psychotic symptoms and progresses in those who later transition to schizophrenia. To understand the implications of this progressive neurobiology on brain function, we have developed a model in rats which we refer to as EDiPs (Enhanced Dopamine in Prodromal schizophrenia). The EDiPs model features a virally mediated increase in dorsal striatal (DS) DA synthesis capacity across puberty and into adulthood. This protocol leads to progressive changes in behaviour and neurochemistry. Our aim in this study was to explore if increased DA synthesis capacity alters the physiology of DA release and DS connectivity. Using fast scan cyclic voltammetry to assess DA release we show that evoked/phasic DA release is increased in the DS of EDiPs rats, whereas tonic/background levels of DA remain unaffected. Using quantitative immunohistochemistry methods to quantify DS synaptic architecture we show a presynaptic marker for DA release sites (Bassoon) was elevated within TH axons specifically within the DS, consistent with the increased phasic DA release in this region. Alongside changes in DA systems, we also show increased density of vesicular glutamate transporter 1 (VGluT1) synapses in the EDiPs DS suggesting changes in cortical connectivity. Our data may prove relevant in understanding the long-term implications for DS function in response to the robust and prolonged increases in DA synthesis uptake and release reported in schizophrenia.
... This suggests that dopamine transmission in the NAc following acute stress is stable even in the context of neuropathic injury. Functional asymmetry in the activity of forebrain dopaminergic pathways arising from the substantia nigra and the VTA has been observed in several experimental contexts [52,53]. These asymmetries are thought to play a role in a range of affective-motivational behaviours that characterise a number of distinctive behavioural phenotypes. ...
The ability to adaptively guide behaviour requires the integration of external information with internal motivational factors. Decision-making capabilities can be impaired by acute stress and is often exacerbated by chronic pain. Chronic neuropathic pain patients often present with cognitive dysfunction, including impaired decision-making. The mechanisms underlying these changes are not well understood but may include altered monoaminergic transmission in the brain. In this study we investigated the relationships between dopamine, serotonin, and their metabolites in key brain regions that regulate motivated behaviour and decision-making. The neurochemical profiles of the medial prefrontal cortex, orbital prefrontal cortex, and nucleus accumbens were analysed using HPLC in rats that received a chronic constriction injury (CCI) of the right sciatic nerve and an acute stress (15-min restraint), prior to an outcome devaluation task. CCI alone significantly decreased dopamine but not serotonin concentrations in the medial prefrontal cortex. By contrast, restraint stress acutely increased dopamine in the medial prefrontal cortex, and the nucleus accumbens; and increased serotonin in the medial prefrontal cortex 2 h later. The sustained dopaminergic and serotonergic responses to acute stress highlight the importance of an animal’s ability to mount an effective coping response. In addition, these data suggest that the impact of nerve injury and acute stress on outcome-devaluation occurs independently of dopaminergic and serotonergic transmission in the medial prefrontal cortex, orbital prefrontal cortex and nucleus accumbens of rats.
... Stress can alter dopamine neurotransmission in the striatum in both DMS and in the dorsolateral striatum (DLS) and alter the ability of animals to adapt flexibly when A-O associations change [7][8][9]. This has been shown in the mesolimbic area [8] and is accompanied by shifts in the lateralization of monoaminergic activity generally [10][11][12][13]. ...
... Endogenous asymmetry in dopaminergic activity within the DS has been found in humans and rodents [11]. In non-stressful conditions, this asymmetry is associated with motor functions such as spatial preferences, direction of rotation or pressing a lever on a particular side of an instrumental apparatus [8,19,20], and can be presented as either left or the right dominance, depending on which limb is used or the direction of the motor movement. ...
Chronic unpredictable stress (CUS) impairs cognitive flexibility in rats, particularly when faced with additional mild acute stress (AS). We tested the hypothesis that this impairment is associated with alterations in dopamine activity in the dorsal striatum driven by corticotropin-releasing-factor receptor type 1 (CRFR1) in the substantia nigra pars compacta (SNpc). In experiment 1, rats received CUS or handling for 14 days, before learning two action-outcome associations (lever presses and food rewards). Learning was assessed using outcome devaluation. Cognitive flexibility was then assessed by reversing the outcome identities followed by a second outcome devaluation test, with half of the rats in each group receiving AS prior to reversal training. Dopamine and its metabolite were quantified in the dorsal striatum and CRFR1 mRNA was quantified in the SNpc. Increased dopaminergic activity in the left dorsal striatum and CRFR1 expression in the left SNpc were associated with resilience to AS in naïve rats but with impairment in CUS+AS rats, suggesting a transition in hemispheric control from left to right as a protective mechanism following CUS. This suggestion was tested in experiment 2, where SNpc CRFR1 was blocked unilaterally prior to AS and reversal training. Blocking CRFR1 in the left medial SNpc impaired cognitive flexibility following AS in naïve rats but restored it in CUS rats. Blocking CRFR1 in the left, but not right, lateral SNpc also impaired cognitive flexibility following AS in naïve rats but had no effect in CUS rats.
... The BG, though not involved directly in movement execution, play an important role in motor learning and selective activation of motor engrams appropriate for the task in question, probably by specification of a cost-function related to a learned movement gain (Turner & Desmurget, 2010). Past fMRI studies demonstrated hemispheric differences in BG activity (e.g., Molochnikov & Cohen, 2014;Zhang et al., 2017). ...
Understanding the impact of variation in lesion topography on the expression of functional impairments following stroke is important, as it may pave the way to modeling structure-function relations in statistical terms while pointing to constraints for adaptive remapping and functional recovery. Multi-perturbation Shapley-value analysis (MSA) is a relatively novel game-theoretical approach for multivariate lesion-symptom mapping. In this methodological paper, we provide a comprehensive explanation of MSA. We use synthetic data to assess the method's accuracy and perform parameter optimization. We then demonstrate its application using a cohort of 107 first-event subacute stroke patients, assessed for upper limb (UL) motor impairment (Fugl-Meyer Assessment scale). Under the conditions tested, MSA could correctly detect simulated ground-truth lesion-symptom relationships with a sensitivity of 75% and specificity of ~90%. For real behavioral data, MSA disclosed a strong hemispheric effect in the relative contribution of specific regions-of-interest (ROIs): poststroke UL motor function was mostly contributed by damage to ROIs associated with movement planning (supplementary motor cortex and superior frontal gyrus) following left-hemispheric damage (LHD) and by ROIs associated with movement execution (primary motor and somatosensory cortices and the ventral brainstem) following right-hemispheric damage (RHD). Residual UL motor ability following LHD was found to depend on a wider array of brain structures compared to the residual motor ability of RHD patients. The results demonstrate that MSA can provide a unique insight into the relative importance of different hubs in neural networks, which is difficult to obtain using standard univariate methods.
... Dopamine coexists and interacts with other neurotransmitters, including various neuropeptides [9] that may participate in the pathogenesis of classic disorders that implicate DA (such as Parkinson's disease and others). Under physiological conditions, DA shows an inter-hemispheric asymmetry [10], which is also obvious in pathological processes such as the first stages of development in Parkinson's disease [11]. However, the response must be comprehensive, as it involves not only the unilateral intra-hemispheric interaction between corticolimbic structures, but also the inter-hemispheric interaction between such structures, as well as the correlation of all of them with plasma elements or with peripheral functions such as cardiac function, as recently reviewed [12]. ...
... In emotional processing, dopamine (DA) plays an essential role: its deterioration, for example in Parkinson's disease, schizophrenia or attention deficit hyperactive disorder [21], can lead to significant emotional consequences that implicate, among others, corticolimbic regions such as medial prefrontal cortex (mPFC), hippocampus (HC) or the amygdala (AM) [7,8]. Under basal physiological conditions, DA shows an inter-hemispheric asymmetry [10], and a possible abnormal brain asymmetry may be part of the pathogenesis of neural disorders involving DA [5,22,23]. ...
In emotional processing, dopamine (DA) plays an essential role, and its deterioration involves important consequences. Under physiological conditions, dopamine exhibits brain asymmetry and coexists with various neuropeptides that can coordinate the processing of brain functions. Brain asymmetry can extend into a broader concept of asymmetric neurovisceral integration, including behavior. The study of the activity of neuropeptide regulatory enzymes (neuropeptidases, NPs) is illustrative. We have observed that the left and right brain areas interact intra- and inter-hemispherically, as well as with peripheral tissues or with physiological parameters such as blood pressure or with behaviors such as turning preference. To obtain data that reflect this integrative behavior, we simultaneously analyzed the impact of left or right brain DA depletion on the activity of various NPs in corticolimbic regions of the left and right hemispheres, such as the medial prefrontal cortex, amygdala and hippocampus, as well as on the plasma activity of the same aminopeptidase activities (APs) and on systolic blood pressure (SBP). Intra- and inter-hemispheric interactions as well as the interactions of NPs from the left or right hemispheres were analyzed with the same plasma APs and the SBP obtained from sham and from left or right lesioned rats. The results demonstrate a complex profile depending on the hemisphere considered. They definitively confirm an asymmetric neurovisceral integration and reveal a higher level of inter-hemispheric corticolimbic interactions including with SBP after left dopamine depletion.
... Animal studies indicate that the dopaminergic mesolimbic system is hemispherically specialized (Molochnikov and Cohen, 2014). When the nucleus dentatus in the cerebellum is electrically stimulated in mice, dopamine release is higher in the right NAcc than in the left NAcc (Holloway et al., 2019). ...
Aggression can have a hedonistic aspect in predisposed individuals labeled as appetitive aggression. The present study investigates the neurobiological correlates of this appetitive type of aggression in non-clinical samples from community. Applying functional magnet resonance imaging (fMRI), we tested whether 20 martial artists compared to 26 controls had a higher activation in the nucleus accumbens (NAcc), a central part of the dopaminergic, mesolimbic reward system. Subjects had to watch violent vs. neutral pictures representing appetitive aggression. The affinity towards hedonistic violence was assessed by the Appetitive and Facilitative Aggression Scale (AFAS). Furthermore, the subjects rated all the pictures with regard to how pleasant and violent they were. The martial artists reported a higher AFAS-score and a more positive perception of violent pictures. On the neural level, across all subjects, there was a significant positive correlation between the AFAS-score and the activation in the left NAcc and an inverse association with the activation of the right NAcc when watching violent compared to neutral pictures. This lateralization effect indicates a different processing of hedonistic aspects of aggression in the two hemispheres.
... Another notable thing was that the different FC of the left and right NAcc in our study may potentially reflect the lateralization of NAcc function. Previous studies suggested that the nigrostriatal system shows symmetrical laterality, while the mesolimbic system shows asymmetrical laterality, which supports hemispheric specialization in rodents [49]. On the other hand, a study investigated that broad interpretations of lateralization of the nucleus accumbens in humans and rodents K Content courtesy of Springer Nature, terms of use apply. ...
PurposeEjaculation represents a crucial component of sexual behavior in men, which is involved in reward functions of certain brain areas including the nucleus accumbens (NAcc). Lifelong premature ejaculation (PE) is one of the most prevalent sexual dysfunctions in men. It is suggested to be related to abnormal brain function. This study aimed to explore changes of the functional connectivity patterns of NAcc and possible correlations of the neuroimaging abnormalities with clinical features in lifelong PE patients.Methods
The sample consisted with 42 lifelong PE patients and 30 healthy controls. All participants underwent functional magnetic resonance imaging scans and clinical symptoms. The functional connectivity (FC) approach was applied to investigate differences of NAcc-seed intrinsic connectivity between two groups and correlation analysis was used to access possible relationships between the imaging findings and clinical features, such as premature ejaculation diagnostic tool (PEDT) or intravaginal ejaculatory latency time (IELT).ResultsResults showed that lifelong PE patients had decreased FC between the NAcc and thalamus, superior temporal pole, superior temporal cortex (STC), inferior frontal gyrus (IFG), orbitofrontal cortex, caudate and putamen. A significantly negative correlation between the PEDT score and NAcc-STC connectivity (r = −0.46) was found in lifelong PE patients, while IELT score positively correlated with the NAcc-IFG connectivity (r = 0.48) and NAcc-thalamus connectivity (r = 0.46).Conclusion
The findings may facilitate a more sophisticated understanding of neural mechanisms of lifelong PE, particularly associated with the NAcc-related intrinsic connectivity during the resting state.
... 27 In healthy individuals, right-left differences have been found in measures of dopamine, the concentration of D1 and D2 receptors, and the binding potential of DA receptors and transporters in the striatum, neocortex, and nucleus accumbens. 164,165 Further, the natural loss of striatal dopamine transporters with age appears to occur evenly on both sides, preserving this asymmetry in older individuals. 166 These differences in the dopaminergic pathways correlate with various functional asymmetries including paw and rotation preference in mice. ...
... 166 These differences in the dopaminergic pathways correlate with various functional asymmetries including paw and rotation preference in mice. 164 Likewise, asymmetry in the nigrostriatal dopaminergic system seems to be a key factor in the lateralization of motor behavior in humans; in one study, the degree of right-hand preference was correlated to greater fluorodopa uptake in the left putamen. 167 This suggests that naturally occurring neurochemical asymmetries in the nigrostriatal pathway may contribute to handedness and may also set up one hemisphere for greater risk of dopamine deficits in neurological disease. ...
The lateralization of the human brain may provide clues into the pathogenesis and progression of neurodegenerative diseases. Though differing in their presentation and underlying pathologies, neurodegenerative diseases are all devastating and share an intriguing theme of asymmetrical pathology and clinical symptoms. Parkinson’s disease, with its distinctive onset of motor symptoms on one side of the body, stands out in this regard, but a review of the literature reveals asymmetries in several other neurodegenerative diseases. Here we review the lateralization of the structure and function of the healthy human brain and the common genetic and epigenetic patterns contributing to the development of asymmetry in health and disease. We specifically examine the role of asymmetry in Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, and interrogate whether these imbalances may reveal meaningful clues about the origins of these diseases. We also propose several hypotheses for how lateralization may contribute to the distinctive and enigmatic features of asymmetry in neurodegenerative diseases, suggesting a role for asymmetry in the choroid plexus, neurochemistry, protein distribution, brain connectivity, and the vagus nerve. Finally, we suggest how future studies may reveal novel insights into these diseases through the lens of asymmetry.
... Notably, such brain wiring might have behavioral consequences, as the side toward which the animal directs its behavior is the manifestation of the difference in the activity of the left and right dopaminergic system. Body movements and behaviors are performed toward the hemisphere with lower dopamine release and away from the hemisphere with higher dopamine release (Arbuthnott and Crow, 1971;Iwamoto et al., 1976;Joyce et al., 1981;Glick et al., 1988;Bourdy et al., 2014;Molochnikov and Cohen, 2014). Therefore, SC, via contralateral RMTg, might contribute to the lateralization of the movement of an animal, based on the direction of incoming sensory stimuli. ...
... Such a neuronal mechanism may underlie the recently described phenomenon, namely that dopaminergic neurons are not only excited by the contralateral rather than the ipsilateral sensory cues, but that there is also a small, yet visible, tendency of DA neurons to decrease their activity when an ipsilateral cue is presented (Engelhard et al., 2019). The proposed brain wiring may have behavioral consequences, since the direction of the movement animals is a manifestation of the difference in the activity of the left and right dopaminergic systems (Molochnikov and Cohen, 2014). The preferred side to which rats rotate or choose to move is contralateral to the hemisphere with higher striatal dopamine concentration (Zimmerberg et al., 1974;Glick et al., 1988). ...
... Accordingly, unilateral disinhibition of the dopaminergic system by RMTg lesion leads to contraversive body rotations (Bourdy et al., 2014;Barrot et al., 2016;Faivre et al., 2020). The basis for these phenomena is high lateralization of the dopaminergic system (i.e., the vast majority of dopaminergic fibers innervate ipsilaterally located striatum; Molochnikov and Cohen, 2014). ...
Dopaminergic (DA) neurons of the midbrain are involved in controlling animals' orienting and approach toward relevant external stimuli. The firing of DA neurons is regulated by many brain structures; however, the sensory input is provided predominantly by the ipsilateral superior colliculus (SC). It is suggested that SC also innervates the contralateral rostromedial tegmental nucleus (RMTg)-the main inhibitory input to DA neurons. Therefore, this study aimed to describe the physiology and anatomy of the SC-RMTg pathway. To investigate the anatomical connections within the circuit of interest, anterograde, retrograde, and transsynaptic tract-tracing studies were performed on male Sprague-Dawley rats. We have observed that RMTg is monosynaptically innervated predominantly by the lateral parts of the intermediate layer of the contralateral SC. To study the physiology of this neuronal pathway, we conducted in vivo electrophysiological experiments combined with optogenetics; the activity of RMTg neurons was recorded using silicon probes while either contralateral or ipsilateral SC was optogenetically stimulated. Obtained results revealed that activation of the contralateral SC excites majority of RMTg neurons, while stimulation of the ipsilateral SC evokes similar proportions of excitatory or inhibitory responses. Consequently, single-unit recordings showed that activation of RMTg neurons innervated by the contralateral SC, or stimulation of contralateral SC-originating axon terminals within the RMTg, inhibits midbrain DA neurons. Together, the anatomy and physiology of the discovered brain circuit suggest its involvement in the animals' orienting and motivation-driven locomotion based on the direction of external sensory stimuli.SIGNIFICANCE STATEMENTDopaminergic neurons are the target of predominantly ipsilateral, excitatory innervation originating from the superior colliculus (SC). However, we demonstrate in our study that SC inhibits dopaminergic neurons' activity on the contralateral side of the brain via the rostromedial tegmental nucleus. In this way, sensory information received by the animal from one hemifield could induce opposite effects on both sides of the dopaminergic system. It was shown that the side to which an animal directs its behavior is a manifestation of asymmetry in dopamine release between left and right striatum. Animals tend to move oppositely to the hemisphere with higher striatal dopamine concentration. This explains how the above-described circuit might guide animals' behavior according to the direction of incoming sensory stimuli.
