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Granule cell layer thickness differed significantly between groups. A: Control rats had a significantly thicker granule cell layer than both ADX groups. There was also a trend for ADXfluoxetine rats to have a thicker granule cell layer than ADX-vehi-
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Long-term adrenalectomy (ADX) causes a nearly complete and selective loss of granule cells in the dentate gyrus (DG) of the hippocampus. Previously, learning and memory deficits have been observed following ADX-induced granule cell degeneration for tasks that require the hippocampus. Our objective here was to determine whether corticosterone (CORT)...
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... ¼ 2.586, P ¼ 0.119. There was an overall effect of ADX with a group comprised of all ADX rats significantly differing from controls, F(1,39) ¼ 30.583, P < 0.001. Control rats had a mean granule cell layer thickness of 6.65 6 0.32 cells, mean thickness was 2.53 6 0.51 cells thick for ADX-vehicle, and 3.63 6 0.45 cells thick for ADX-fluoxetine rats (Fig. ...
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... Furthermore, any disturbance in the levels of such hormones directly affects the survival of neurons, and this might be reflected in the cognitive capability of the animals. The hippocampus is known for its major role in learning and memory, and several investigations, including our own, indicated a decline in memory performance tasks and learning in long-term ADX rats, highlighting the possibility of the involvement of neuronal damage [7,[30][31][32]. ...
... Moreover, Conrad and Roy [58] showed that after long-term adrenalectomy, the ADX rats exhibited difficulties in acquiring new spatial memory. Furthermore, Spanswick et al. [31] showed the inability to reverse such deficit in the spatial memory of long-term ADX rats by chronic treatment (6 weeks) with corticosterone, or by an alternative neurogenic com-pound, fluoxetine. The latter finding indicates the crucial role of hippocampal formation in building memories, and acquiring new information. ...
The development of animal models to study cell death in the brain is a delicate task. One of the models, that was discovered in the late eighties, is the induction of neurodegeneration through glucocorticoid withdrawal by adrenalectomy in albino rats. Such a model is one of the few noninvasive models for studying neurodegeneration. In the present study, using stereological technique and ultrastructural examination, we aimed to investigate the impact of short-term adrenalectomy (2 weeks) on different hippocampal neuronal populations in Wistar rats. In addition, the underlying mechanism(s) of degeneration in these neurons were investigated by measuring the levels of insulin-like growth factor-1 (IGF-1) and β-nerve growth factor (β-NGF). Moreover, we examined whether the biochemical and histological changes in the hippocampus, after short-term adrenalectomy, have an impact on the cognitive behavior of Wistar rats. Stereological counting in the hippocampus revealed significant neuronal deaths in the dentate gyrus and CA4/CA3, but not in the CA2 and CA1 areas, 7 and 14 days post adrenalectomy. The ultrastructural examinations revealed degenerated and degenerating neurons in the dentate, as well as CA4, and CA3 areas, over the course of 3, 7 and 14 days. The levels of IGF-1 were significantly decreased in the hippocampus of ADX rats 24 h post adrenalectomy, and lasted over the course of two weeks. However, β-NGF was not affected in rats. Using a passive avoidance task, we found a cognitive deficit in the ADX compared to the SHAM operated rats over time (3, 7, and 14 days). In conclusion, both granule and pyramidal cells were degenerated in the hippocampus following short-term adrenalectomy. The early depletion of IGF-1 might play a role in hippocampal neuronal degeneration. Consequently, the loss of the hippocampal neurons after adrenalectomy leads to cognitive deficits.
... In order to provide mice with chronic cognitive stimulation, we trained half of the mice on a repeated acquisition and performance testing variant of the Morris Water Task (MWT) (Spanswick et al., 2007). In this version of the task, the hidden escape platform is . ...
Memory storage and retrieval are shaped by past experiences. Prior learning and memory episodes have numerous impacts on brain structure from micro to macroscale. Previous experience with specific forms of learning increases the efficiency of future learning. It is less clear whether such practice effects on one type of memory might also have transferable effects to other forms of memory. Different forms of learning and memory rely on different brain-wide networks but there are many points of overlap in these networks. Enhanced structural or functional connectivity as a result of one type of learning may be transferable to another type of learning due to this overlap in memory networks. Here, we investigated the impact of prior chronic spatial training on the task-specific functional connectivity related to subsequent contextual fear memory recall in mice. Our results show that mice exposed to prior spatial training exhibited decreased brain-wide activation compared to control mice during the retrieval of a context fear memory. With respect to functional connectivity, we observed changes in several network measures notably an increase in global efficiency. Interestingly, we also observed an increase in network resilience based on simulated targeted node deletion. Overall this study suggests that chronic learning has transferable effects on the functional connectivity networks of other types of learning and memory. The generalized enhancements in network efficiency and resilience suggest that learning itself may protect brain networks against deterioration.
... The hippocampus is known for its major role in learning and memory, several investigations indicated a decline in memory performance tasks in ADX rats which highlights the possibility of the involvement of neuronal damage in the poor cognitive performance 12,[27][28][29] . Therefore, we aimed in the current study to investigate cell death in the hippocampus after short-term adrenalectomy and explore whether both granule and pyramidal cells are vulnerable to the absence of glucocorticoids. ...
... Moreover, Conrad and Roy 55 showed that after long-term adrenalectomy, the ADX rats exhibited di culties in acquiring a new spatial memory. Furthermore, Spanswick et al. 29 showed the inability to reverse such de cit in the spatial memory of long-term ADX rats by chronic treatment (6 weeks) with corticosterone or by an alternative neurogenic compound, Fluoxetine. The later nding indicates the crucial role of hippocampal formation in building memories and acquiring new information. ...
In the current study we investigated the impact of short-term adrenalectomy on hippocampal neurons of Wistar rats. In addition, the underlying mechanism(s) of degeneration in these neurons was investigated by measuring the levels of insulin-like growth factor-1 and β-nerve growth factor. Moreover, we investigated the cognitive behavior in these rats.
The stereological counting in the hippocampus revealed a significant neuronal death in the dentate gyrus and CA3, but not in the CA2 and CA1, area 7 and 14 days post adrenalectomy. The ultrastructural examinations revealed degenerated and degenerating neurons only in the dentate as well as CA4, and CA3 areas over the course of 3, 7 and 14 days.
The levels of IGF-1 were significantly decreased in the hippocampus of ADX rats 12 h post adrenalectomy and lasted over the course of two weeks. However, β-NGF was significantly reduced in ADX rats only at 14 days postoperatively. Using passive avoidance test we found a cognitive deficit in the ADX compared to the sham operated rats over time.
In conclusion, both granule and pyramidal cells were degenerated in the hippocampus following short-term adrenalectomy. The early depletion of IGF-1 might play a role in the hippocampal neuronal degeneration. Consequently, the loss of the hippocampal neurons after adrenalectomy leads to cognitive deficits.
... Adrenalectomized rats showed an impairment in working memory, suggesting that endogenous glucocorticoids are essential for maintaining prefrontal cortical cognitive function (Mizoguchi et al., 2004). Adrenalectomy also caused granule cell degeneration in the hippocampus, causing spatial memory deficits (Spanswick et al., 2007). Using DEX, Rashidy-Pour et al. (2004) reported that when DEX was administered 30 min before memory retrieval, the expression of the defensive responses was impaired. ...
Behavioral and neuroendocrine responses following threatening situations promote the release of corticosterone, which is known to modulate trauma-related learning and memory process. However, it remains unknown whether the aversive learning generated by interoceptive fear conditioning is affected by glucocorticoid modulation. Therefore, the present study aimed to investigate the role of dexamethasone suppression in encoding and expression of pentylenetetrazole-induced olfactory fear conditioning (OFC) and in contextual second-order conditioning promoted by the conditioned odor. Adult male Long-Evans rats were treated with dexamethasone 60 min before the encoding or the expression in both OFC and contextual second-order conditioning. Dexamethasone treatment impaired encoding and expression of the OFC, but failed to impair encoding and expression of the contextual second-order conditioning. Altogether, our results show that although OFC and thereafter contextual second-order conditioning may allow the study of traumatic memories, each order of conditioning seems to present specific features related to their pharmacological modulation. These findings highlight the importance of addressing the role of neuromodulatory systems in first-order and second-order conditioning to gain a better understanding of these phenomena and support future therapies related to traumatic memories.
... dexamethasone, DEX) glucocorticoids are elevated sufficiently to activate glucocorticoid receptors (GR), which are ligand-activated transcription factors (de Kloet et al., 2005). An additional twist to the cerebral actions of GC stems from observations that GC depletion causes neuronal atrophy and cognitive deficits (Sloviter et al., 1989;Conrad et al., 1997;Sousa et al., 1997;Spanswick et al., 2007). These effects are attributed to the fact that low physiological levels of CORT predominantly act via mineralocorticoid receptors (MR) that appear to be neuroprotective (Hassan et al., 1996;Almeida et al., 2000) and influence cognition (de Kloet et al., 1999). ...
Steroid hormones secreted by the gonads (sex steroids) and adrenal glands (glucocorticoids, GC) are known to influence brain structure and function. While levels of sex steroids wane in late adulthood, corticosteroid levels tend to rise in many individuals due to age-related impairments in their feedback on central mechanisms regulating adrenal function. These fluctuations in sex and adrenal steroid secretion may be relevant to age-related neurodegenerative disorders such as Alzheimer’s disease (AD) in which hyperphosphorylation of Tau protein is a key pathological event. We here report that both, long-term GC deprivation (by adrenalectomy) and exogenous GC administration with natural or synthetic glucocorticoid receptor ligands (corticosterone and dexamethasone, respectively) induce Tau hyperphosphorylation in the hippocampus and frontocortical regions at epitopes associated with disruption of cytoskeletal and synaptic function. Interestingly, we observed that the changes in Tau induced by manipulation of the GC milieu of male rats were exacerbated by testosterone depletion (by orchiectomy). While this finding supports previous suggestions of a neuroprotective role of male sex hormones, this is the first study to address interactions between adrenal and sex steroids on Tau hyperphosphorylation and accumulation that are known to endanger neuronal function and plasticity. These results are particularly important for understanding the mechanisms that can precipitate AD because, besides being modulated by age, GC are elevated by stress, a phenomenon now established as a trigger of deficits in neural plasticity and survival, cognitive behaviour and AD-like Tau pathology.
... The exceptional vulnerability of the DG is also evidenced in other human pathologies, such as frontotemporal lobe degeneration, Alzheimer's disease, and adrenal insufficiency (Maehlen and Torvik, 1990;Armstrong et al., 2012;Collins et al., 2012;Kovacs et al., 2013;Takeda and Tamano, 2018) and in rodent models of these and other pathologies that are often associated with enhanced neurogenesis (Spanswick et al., 2007(Spanswick et al., , 2011Watanabe et al., 2016;Choi et al., 2017;Tu et al., 2018;F. Wang et al., 2018). ...
... An intrinsic mechanism to cope with neuronal damage is of particular significance in the case of the DG given its exceptional vulnerability to many insults, such as virus-induced encephalitis (Wu et al., 2013), exposure to chemicals (Bruccoleri et al., 1998;Choi et al., 2014Choi et al., , 2017, adrenalectomy/adrenal insufficiency (Spanswick et al., 2007(Spanswick et al., , 2011Izumida et al., 2017), and Alzheimer's disease and frontotemporal lobe degeneration (Small et al., 2011;Armstrong et al., 2012;Adler et al., 2018). Our study adds yet another example for a selective DG vulnerability, namely, selective apoptosis of DG neurons following prolonged exposure to ectopic VEGF (a situation that can be physiologically relevant in the case of CNS tumors). ...
Multiple insults to the brain lead to neuronal cell death, thus raising the question to what extent can lost neurons be replenished by adult neurogenesis. Here we focused on the hippocampus and especially the dentate gyrus (DG), a vulnerable brain region and one of the two sites where adult neuronal stem cells (NSCs) reside. While adult hippocampal neurogenesis was extensively studied with regard to its contribution to cognitive enhancement, we focused on their underestimated capability to repair a massively injured, nonfunctional DG. To address this issue, we inflicted substantial DG-specific damage in mice of either sex either by diphtheria toxin-based ablation of >50% of mature DG granule cells (GCs) or by prolonged brain-specific VEGF overexpression culminating in extensive, highly selective loss of DG GCs (thereby also reinforcing the notion of selective DG vulnerability). The neurogenic system promoted effective regeneration by increasing NSCs proliferation/survival rates, restoring a nearly original DG mass, promoting proper rewiring of regenerated neurons to their afferent and efferent partners, and regaining of lost spatial memory. Notably, concomitantly with the natural age-related decline in the levels of neurogenesis, the regenerative capacity of the hippocampus also subsided with age. The study thus revealed an unappreciated regenerative potential of the young DG and suggests hippocampal NSCs as a critical reservoir enabling recovery from catastrophic DG damage.
... There is a circuit in hippocampus with input from the Entorhinal Cortex (EC) that forms connections with the DG and output back to the EC through CA1. Damage of any part of this circuit will affect the process of learning and memory [30][31][32][33] . In the present study, dendritic shaft and spine morphology in CA1 and DG regions were investigated, which helped us understand whether and how BPA affects hippocampal input/output and efficiency. ...
Bisphenol-A (BPA, 4, 4′-isopropylidene-2-diphenol), a synthetic xenoestrogen that widely used in the production of polycarbonate plastics, has been reported to impair hippocampal development and function. Our previous study has shown that BPA exposure impairs Sprague-Dawley (SD) male hippocampal dendritic spine outgrowth. In this study, the sex-effect of chronic BPA exposure on spatial memory in SD male and female rats and the related synaptic mechanism were further investigated. We found that chronic BPA exposure impaired spatial memory in both SD male and female rats, suggesting a dysfunction of hippocampus without gender-specific effect. Further investigation indicated that BPA exposure causes significant impairment of dendrite and spine structure, manifested as decreased dendritic complexity, dendritic spine density and percentage of mushroom shaped spines in hippocampal CA1 and dentate gyrus (DG) neurons. Furthermore, a significant reduction in Arc expression was detected upon BPA exposure. Strikingly, BPA exposure significantly increased the mIPSC amplitude without altering the mEPSC amplitude or frequency, accompanied by increased GABAARβ2/3 on postsynaptic membrane in cultured CA1 neurons. In summary, our study indicated that Arc, together with the increased surface GABAARβ2/3, contributed to BPA induced spatial memory deficits, providing a novel molecular basis for BPA achieved brain impairment.
... The remaining multiparous and nulliparous rats were behaviorally trained on 2 versions of the Morris water maze starting on day 12 of hormone and vehicle treatments. To test spatial working memory, the location of the hidden platform was moved every 2 days (Moving Platform version of the Morris water maze, Keith et al., 2007;Spanswick et al., 2007). To test spatial reference memory, the standard protocol was used where the location of the hidden platform remained fixed for 4 days (Stationary Platform version of the Morris water maze). ...
... Also, the plasma corticosterone level of the group which was given aminoglutethimide + dexamethasone phosphate was significantly higher than that of the group which was given aminoglutethimide only, but was significantly lower than the control group [17]. Spanwick et al. have shown that when 1 mg cortisone was administered to adrenalectomized rats, their daily cortisone levels were the same as rats with intact adrenals [18]. In light of the above information, we decided to use aminoglutethimide in our study in performing chemical adrenalectomy. ...
Today corticosteroids are employed for the treatment of various inner ear disorders. In this study we have investigated probable changes in hearing functions resulting from a deficiency of systemic steroid secretions.
Twenty four healthy female rats were used in our study, allocated into three groups (medical adrenalectomy, medical adrenalectomy+dexamethasone, no treatment). Audiological evaluations were conducted at the beginning of the study and on days 7, 14 and 21. Blood samples were taken at the beginning and at the end of the study and blood corticosterone levels were determined.
While there were no significant differences between the basal, 7th, 14th and 21st day DPOAE values of group 1, their ABR threshold values showed significant increases. In group 2, there were no significant differences between the basal, 7th, 14th and 21st day DPOAE values. ABR thresholds of group 2 showed significant increases on days 7 and 14 as compared to their basal values, but there were no significant differences between the 21st day and basal ABR threshold values. There were no significant differences between the basal cortisol levels of the three groups. The mean cortisol level of group 1 on day 21 was found to be significantly lower than those of groups 2 and 3.
The results of the study demonstrated that there were no significant changes in DPOAE values with the cessation of cortisol secretion, while there was a progressive increase in ABR thresholds, which could be overcome with cortisone replacement.
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... Chronic CORT administration might increase circulating GC levels in the CA1 region of the rat hippocampus, resulting in impairment of long-term potentiation and spatial learning and memory in the MWM [33]. The beneficial effects of acupuncture on CORT-induced learning and memory deficits could be related to an increase in septohippocampal cholinergic function and prevention of degeneration in the cholinergic neuronal population of the septohippocampal fibers in mediating cognitive processes [34]. ...
The purpose of this study was to examine whether acupuncture improves spatial cognitive impairment induced by repeated corticosterone (CORT) administration in rats. The effect of acupuncture on the acetylcholinergic system was also investigated in the hippocampus. Male rats were subcutaneously injected with CORT (5 mg/kg) once daily for 21 days. Acupuncture stimulation was performed at the HT7 (Sinmun) acupoint for 5 min before CORT injection. HT7 acupoint is located at the end of transverse crease of ulnar wrist of forepaw. In CORT-treated rats, reduced spatial cognitive function was associated with significant increases in plasma CORT level (+36%) and hippocampal CORT level (+204%) compared with saline-treated rats. Acupuncture stimulation improved the escape latency for finding the platform in the Morris water maze. Consistently, the acupuncture significantly alleviated memory-associated decreases in cholinergic immunoreactivity and mRNA expression of BDNF and CREB in the hippocampus. These findings demonstrate that stimulation of HT7 acupoint produced significant neuroprotective activity against the neuronal impairment and memory dysfunction.
