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Administration of exercise mimetic drugs could be a novel therapeutic approach to combat comorbid neurodegeneration and metabolic syndromes. Adiponectin is an adipocyte-secreted hormone. In addition to its antidiabetic effect, adiponectin mediates the antidepressant effect of physical exercise associated with adult hippocampal neurogenesis. The antidiabetic effect of the adiponectin receptor agonist AdipoRon has been demonstrated, but its potential pro-cognitive and neurotrophic effects in the hippocampus under diabetic condition are still unclear. This study reported that chronic AdipoRon treatment for 2 weeks improved hippocampal-dependent spatial recognition memory in streptozotocin-induced diabetic mice. Besides, AdipoRon treatment increased progenitor cell proliferation and neuronal differentiation in the hippocampal dentate gyrus (DG) of diabetic mice. Furthermore, AdipoRon treatment significantly increased dendritic complexity, spine density, and N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) in the dentate region, and increased BDNF levels in the DG of diabetic mice. AdipoRon treatment activated AMPK/PGC-1α signalling in the DG, whereas increases in cell proliferation and LTP were not observed when PGC-1α signalling was pharmacologically inhibited. In sum, chronic AdipoRon treatment partially mimics the benefits of physical exercise for learning and memory and hippocampal neuroplasticity in the diabetic brain. The results suggested that AdipoRon could be a potential physical exercise mimetic to improve hippocampal plasticity and hence rescue learning and memory impairment typically associated with diabetes. Supplementary Information The online version contains supplementary material available at 10.1007/s12035-021-02441-7.

Background: It is becoming increasingly recognized that there is significant interneuron degeneration in Alzheimer's disease. As the hippocampus is integral for learning and memory, we performed a ...

Background and Objectives: We examined how acute ethanol (EtOH) exposure affects long term depression (LTD) in the dentate gyrus (DG) of the hippocampus in juvenile rats. EtOH is thought to directly modulate n-methyl-D-aspartate receptor (NMDAr) currents, which are believed important for LTD induction. LTD in turn is believed to play an important developmental role in the hippocampus by facilitating synaptic pruning. Methods: Hippocampal slices (350μm) were obtained at post-natal day (PND) 14, 21, or 28. Field EPSPs (excitatory post-synaptic potential) or whole-cell EPSCs (excitatory post-synaptic conductance) were recorded from the DG (dentate gyrus) in response to medial perforant path activation. Low-frequency stimulation (LFS; 900 pulses; 120 s pulse) was used to induce LTD. Results: Whole-cell recordings indicated that EtOH exposure at 50mM did not significantly impact ensemble NMDAr EPSCs in slices obtained from animals in the PND14 or 21 groups, but it reliably produced a modest inhibition in the PND28 group. Increasing the concentration to 100 mM resulted in a modest inhibition of NMDAr EPSCs in all three groups. LTD induction and maintenance was equivalent in magnitude in all three age groups in control conditions, however, and surprisingly, NMDA antagonist AP5 only reliably blocked LTD in the PND21 and 28 age groups. The application of 50 mM EtOH attenuated LTD in all three age groups, however increasing the concentration to 100 mM did not reliably inhibit LTD. Conclusions: These results indicate that the effect of EtOH on NMDAr-EPSCs recorded from DGCs is both age and concentration dependent in juveniles. Low concentrations of EtOH can attenuate, but did not block LTD in the DG. The effects of EtOH on LTD do not align well with it’s effects on NNMDA receptors.

Cannabinoid receptors are widely expressed throughout the hippocampal formation, but are particularly dense in the dentate gyrus (DG) subregion. We, and others, have shown in mice that cannabinoid type 1 receptors (CB1Rs) are involved in a long-term depression (LTD) that can be induced by prolonged 10 Hz stimulation of the medial perforant path (MPP)-granule cell synaptic input to the DG. Here, we extend this work to examine the involvement of CB1Rs in other common forms of LTD in the hippocampus of juvenile male and female Sprague–Dawley rats (Rattus norvegicus). We found, as in mice, that prolonged 10 Hz stimulation (6000 pulses) could reliably induce a form of LTD that was dependent upon CB1R activation. In addition, we also discovered a role for both CB1R and mGluR proteins in LTD induced with 1 Hz low-frequency stimulation (1 Hz-LTD; 900 pulses) and in LTD induced by bath application of the group I mGluR agonist (RS)-3,5-Dihydroxyphenylglycine (DHPG; DHPG-LTD). This study elucidates an essential role for endocannabinoid receptors in a number of forms of LTD in the rat DG, and identifies a novel role for CB1Rs as potential therapeutic targets for conditions that involve impaired LTD in the DG.

Fetal alcohol spectrum disorder (FASD) is caused by prenatal exposure to ethanol and has been linked to neurodevelopmental impairments. Alcohol has the potential to alter some of the epigenetic components that play a critical role during development. Previous studies have provided evidence that prenatal exposure to ethanol results in abnormal epigenetic patterns (i.e., hypomethylation) of the genome. The aim of this study was to determine how prenatal exposure to ethanol in rats affects the hippocampal levels of expression of two important brain epigenetic transcriptional regulators involved in synaptic plasticity and memory consolidation: methyl CpG-binding protein 2 (MeCP2) and histone variant H2A.Z. Unexpectedly, under the conditions used in this work we were not able to detect any changes in MeCP2. Interestingly, however, we observed a significant decrease in H2A.Z, accompanied by its chromatin redistribution in both female and male FASD rat pups. Moreover, the data from reverse-transcription qPCR later confirmed that this decrease in H2A.Z is mainly due to down-regulation of its H2A.Z-2 isoform gene expression. Altogether, these data provide strong evidence that prenatal exposure to ethanol alters histone variant H2A.Z during neurogenesis of rat hippocampus.

AdipoRon, an adiponectin receptor agonist, elicits similar antidiabetic, anti-atherogenic, and anti-inflammatory effects on mouse models as adiponectin does. Since AdipoRon can cross the blood-brain barrier, its chronic effects on regulating hippocampal function are yet to be examined. This study investigated whether AdipoRon treatment promotes hippocampal neurogenesis and spatial recognition memory in a dose-dependent manner. Adolescent male C57BL/6J mice received continuous treatment of either 20 mg/kg (low dose) or 50 mg/kg (high dose) AdipoRon or vehicle intraperitoneally for 14 days, followed by the open field test to examine anxiety and locomotor activity, and the Y maze test to examine hippocampal-dependent spatial recognition memory. Immunopositive cell markers of neural progenitor cells, immature neurons, and newborn cells in the hippocampal dentate gyrus were quantified. Immunosorbent assays were used to measure the serum levels of factors that can regulate hippocampal neurogenesis, including adiponectin, brain-derived neurotrophic factor (BDNF), and corticosterone. Our results showed that 20 mg/kg AdipoRon treatment significantly promoted hippocampal cell proliferation and increased serum levels of adiponectin and BDNF, though there were no effects on spatial recognition memory and locomotor activity. On the contrary, 50 mg/kg AdipoRon treatment impaired spatial recognition memory, suppressed cell proliferation, neuronal differentiation, and cell survival associated with reduced serum levels of BDNF and adiponectin. The results suggest that a low-dose AdipoRon treatment promotes hippocampal cell proliferation, while a high-dose AdipoRon treatment is detrimental to the hippocampus function.

Cannabinoid type-1 (CB1 ) receptors are widely distributed in the brain and play important roles in astrocyte function and the modulation of neuronal synaptic transmission and plasticity. However, it is currently unknown how CB1 receptor expression in astrocytes is affected by long-term exposure to stressors. Here we examined CB1 receptors in astrocytes of ethanol (EtOH)-exposed adolescent mice to determine its effect on CB1 receptor localization and density in adult brain. 4-8-week-old male mice were exposed to 20 percent EtOH over a period of 4 weeks, and receptor localization was examined after 4 weeks in the hippocampal CA1 stratum radiatum by pre-embedding immunoelectron microscopy. Our results revealed a significant reduction in CB1 receptor immunoparticles in astrocytic processes of EtOH-exposed mice when compared with controls (positive astrocyte elements: 21.50 ± 2.80 percent versus 37.22 ± 3.12 percent, respectively), as well as a reduction in particle density (0.24 ± 0.02 versus 0.35 ± 0.02 particles/μm). The majority of CB1 receptor metal particles were in the range of 400-1200 nm from synaptic terminals in both control and EtOH. Altogether, the decrease in the CB1 receptor expression in hippocampal astrocytes of adult mice exposed to EtOH during adolescence reveals a long lasting effect of EtOH on astrocytic CB1 receptors. This deficiency may also have negative consequences for synaptic function.

The hippocampus is a brain structure known to play a central role in cognitive function (namely learning and memory) as well as mood regulation and affective behaviors due in part to its ability to undergo structural and functional changes in response to intrinsic and extrinsic stimuli. While structural changes are achieved through modulation of hippocampal neurogenesis as well as alterations in dendritic morphology and spine remodeling, functional (i.e., synaptic) changes can be noted through the strengthening (i.e., long-term potentiation) or weakening (i.e., long-term depression) of the synapses. While age, hormone homeostasis, and levels of physical activity are some of the factors known to module these forms of hippocampal plasticity, the exact mechanisms through which these factors interact with each other at a given moment in time are not completely understood. It is well known that hormonal levels vary throughout the lifespan of an individual and it is also known that physical exercise can impact hormonal homeostasis. Thus, it is reasonable to speculate that hormone modulation might be one of the various mechanisms through which physical exercise differently impacts hippocampal plasticity throughout distinct periods of an individual's life. The present review summarizes the potential relationship between physical exercise and different types of hormones (namely sex, metabolic, and stress hormones) and how this relationship may mediate the effects of physical activity during three distinct life periods, adolescence, adulthood, and senescence. Overall, the vast majority of studies support a beneficial role of exercise in maintaining hippocampal hormonal levels and consequently, hippocampal plasticity, cognition, and mood regulation.

Background Marijuana and alcohol are both substances that, when used during pregnancy, may have profound effects on the developing fetus. There is evidence to suggest that both drugs have the capacity to affect working memory, one function of the hippocampal formation; however, there is a paucity of data on how perinatal exposure to alcohol or cannabis impacts the process of adult neurogenesis. Methods This systematic review examines immunohistochemical data from adult rat and mouse models that assess perinatal alcohol or perinatal marijuana exposure. A comprehensive list of search terms was designed and used to search 3 separate databases. All results were imported to Mendeley and screened by 2 authors. Consensus was reached on a set of final papers that met the inclusion criteria, and their results were summarized. Results Twelve papers were identified as relevant, 10 of which pertained to the effects of perinatal alcohol on the adult hippocampus, and 2 pertained to the effects of perinatal marijuana on the adult hippocampus. Cellular proliferation in the dentate gyrus was not affected in adult rats and mice exposed to alcohol perinatally. In general, perinatal alcohol exposure did not have a significant and reliable effect on the maturation and survival of adult born granule neurons in the dentate gyrus. In contrast, interneuron numbers appear to be reduced in the dentate gyrus of adult rats and mice exposed perinatally to alcohol. Perinatal marijuana exposure was also found to reduce inhibitory interneuron numbers in the dentate gyrus. Conclusions Perinatal alcohol exposure and perinatal marijuana exposure both act on inhibitory interneurons in the hippocampal formation of adult rats. These findings suggest simultaneous perinatal alcohol and marijuana exposure (SAM) may have a dramatic impact on inhibitory processes in the dentate gyrus.

Hippocampal slices are widely used for in vitro electrophysiological experiments to study underlying mechanisms for synaptic transmission and plasticity, and there is a growing appreciation for sex differences in synaptic plasticity. To date, several studies have shown that the process of making slices from male animals can induce synaptogenesis in cornu ammonis area 1 (CA1) pyramidal cells, but there is a paucity of data for females and other brain regions. In the current study we use microcrystals of the lipophilic carbocyanine dye DiI (1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate) to stain individual neurons in the CA1 and dentate gyrus (DG) hippocampal subfields of postnatal day 21 male and female rats. We show that the preparation of sections for electrophysiology produces significant increases in spines in sections obtained from females, similar to that observed in males. We also show that the procedures used for in vitro electrophysiology also result in significant spine increases in the DG and CA1 subfields. These results demonstrate the utility of this refined DiI procedure for staining neuronal dendrites and spines. They also show, for the first time, that in vitro electrophysiology slice preparations enhance spine numbers on hippocampal cells equivalently in both juvenile females and males.NEW & NOTEWORTHY This study introduces a new DiI technique that elucidates differences in spine numbers in juvenile female and male hippocampus, and shows that slice preparations for hippocampal electrophysiology in vitro may mask these differences.

BACKGROUND: The hippocampus is particularly vulnerable to the teratogenic effects of prenatal ethanol exposure (PNEE), and hippocampal structural and functional deficits are thought to contribute to the learning and memory deficits that are a hallmark feature of fetal alcohol spectrum disorders (FASDs). METHOD: Sprague-Dawley dams were exposed to a liquid diet that contained EtOH (35.5% EtOH-derived calories) throughout gestation, and then PNEE juvenile (P21-28) male and female offspring were used for in vitro electrophysiological recordings. We examined long-term potentiation (LTP), long-term depression (LTD) and depotentiation in the medial perforant path (MPP) input to the dentate gyrus (DG) to determine the impact of PNEE on the dynamic range of bidirectional synaptic plasticity in both sexes. RESULTS: PNEE reduced the responsiveness of the DGs of male but not in female offspring, and this effect was no longer apparent when GABAergic signalling was inhibited. There was also a sex-specific LTD impairment in males, but increasing the duration of the conditioning stimulus could overcome this deficit. The magnitude of LTP was also reduced, but in both sexes following PNEE. This appears to be an increase in the threshold for induction, not in capacity, as the level of LTP induced in PNEE animals was increased to control-levels when additional conditioning stimuli were administered. CONCLUSIONS: These data are the first to describe, in a single study, the impact of PNEE on the dynamic range of bidirectional synaptic plasticity in the juvenile DG in both males and in females. The data suggest that PNEE increases the threshold for LTP in the DG in both sexes, but produces a sex-specific increase in the threshold for LTD in males These alterations reduce the dynamic range for synaptic plasticity in both sexes.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. It is caused by the overexpansion of cytosine-guanine-guanine (CGG) trinucleotide in Fmr1 gene, resulting in complete loss of the fragile X mental retardation protein (FMRP). Previous studies using Fmr1 knockout (Fmr1 KO) mice have suggested that a N-methyl-D-aspartate receptors (NMDAR) hypofunction in the hippocampal dentate gyrus may partly contribute to cognitive impairments in FXS. Since activation of NMDAR plays an important role in dendritic arborization during neuronal development, we examined whether deficits in NMDAR function are associated with alterations in dendritic complexity in the hippocampal dentate region. The dentate granule cell layer (GCL) presents active postnatal neurogenesis, and consists of a heterogenous neuronal population with gradient ages from the superficial to its deep layer. Here, we show that neurons with multiple primary dendrites that reside in the outer GCL of Fmr1 KO mice display significantly smaller NMDAR excitatory post-synaptic currents (EPSCs) and a higher α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to NMDA ratio in comparison to their wild-type counterparts. These deficits were associated with a significant decrease in dendritic complexity, with both dendritic length and number of intersections being significantly reduced. In contrast, although neurons with a single primary dendrite resided in the inner GCL of Fmr1 KO mice had a trend toward a reduction in NMDAR EPSCs and a higher AMPA/NMDA ratio, no alterations were found in dendritic complexity at this developmental stage. Our data indicate that the loss of FMRP causes NMDAR deficits and reduced dendritic complexity in granule neurons with multiple primary dendrites which are thought to be more mature in the GCL.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability that can be traced to a single gene mutation. This disorder is caused by the hypermethylation of the Fmr1 gene, which impairs translation of Fragile X Mental Retardation Protein (FMRP). In Fmr1 knockout (KO) mice, the loss of FMRP has been shown to negatively impact adult hippocampal neurogenesis, and to contribute to learning, memory, and emotional deficits. Conversely, physical exercise has been shown to enhance cognitive performance, emotional state, and increase adult hippocampal neurogenesis. In the current experiments, we used two different voluntary running paradigms to examine how exercise impacts adult neurogenesis in the dorsal and ventral hippocampal dentate gyrus (DG) of Fmr1 KO mice. Immunohistochemical analyses showed that short-term (7 day) voluntary running enhanced cell proliferation in both wild-type (WT) and Fmr1 KO mice. In contrast, long-term (28 day) running only enhanced cell proliferation in the whole DG of WT mice, but not in Fmr1 KO mice. Interestingly, cell survival was enhanced in both WT and Fmr1 KO mice following exercise. Interestingly we found that running promoted cell proliferation and survival in the ventral DG of WTs, but promoted cell survival in the dorsal DG of Fmr1 KOs. Our data indicate that long-term exercise has differential effects on adult neurogenesis in ventral and dorsal hippocampi in Fmr1 KO mice. These results suggest that physical training can enhance hippocampal neurogenesis in the absence of FMRP, may be a potential intervention to enhance learning and memory and emotional regulation in FXS.

Background Our previous work has shown that exposure to the stress hormone corticosterone (40 mg/kg CORT) for two weeks induces dendritic atrophy of pyramidal neurons in the hippocampal CA3 region and behavioral deficits. However, it is unclear whether this treatment also affects the dentate gyrus (DG), a subregion of the hippocampus comprising a heterogeneous population of young and mature neurons. Objective We examined the effect of CORT treatment on the dendritic complexity of mature and young granule cells in the DG. Methods We utilized a Golgi staining method to investigate the dendritic morphology and spine density of young neurons in the inner granular cell layer (GCL) and mature neurons in the outer GCL in response to CORT application. The expressions of glucocorticoid receptors during neuronal maturation were examined using Western blot analysis in a primary hippocampal neuronal culture. Results Sholl analysis revealed that CORT treatment decreased the number of intersections and shortened the dendritic length in mature, but not young, granule cells. However, the spine density of mature and young neurons was not affected. Western blot analysis showed a progressive increase in the protein levels of glucocorticoid receptors (GRs) in the cultured primary hippocampal neurons during neuronal maturation. Conclusion These data suggest that mature neurons are likely more vulnerable to chronic exposure to CORT; this may be due to their higher expression of GRs when compared to younger DG neurons.

The hippocampus plays an integral role in certain aspects of cognition. Hippocampal structural plasticity and in particular adult hippocampal neurogenesis can be influenced by several intrinsic and extrinsic factors. Here we review how hormones (i.e., intrinsic modulators) and physical exercise (i.e., an extrinsic modulator) can differentially modulate hippocampal plasticity in general and adult hippocampal neurogenesis in particular. Specifically, we provide an overview of the effects of sex hormones, stress hormones, and metabolic hormones on hippocampal structural plasticity and adult hippocampal neurogenesis. In addition, we also discuss how physical exercise modulates these forms of hippocampal plasticity, giving particular emphasis on how this modulation can be affected by variables such as exercise regime, duration, and intensity. Understanding the neurobiological mechanisms underlying the modulation of hippocampal structural plasticity by intrinsic and extrinsic factors will impact the design of new therapeutic approaches aimed at restoring hippocampal plasticity following brain injury or neurodegeneration.

Guanosine is a purine nucleoside that occurs naturally in the central nervous system, exerting trophic effects. Given its neuroprotective properties, the potential of guanosine as an antidepressant has been recently examined. Within this context, the present study sought to investigate the effects of chronic treatment with guanosine on the tail suspension test (TST), open field test and adult hippocampal neurogenesis. Swiss mice were administered guanosine for 21 days (5 mg/kg/day, p.o.) and subsequently submitted to the TST and open-field test. Following behavioural testing, animals were killed and the brains were processed for immunohistochemical analyses of hippocampal cell proliferation and neuronal differentiation. Animals treated with guanosine showed a reduction in immobility time in the TST without alterations in locomotor activity, confirming the antidepressant-like effect of this compound. Quantitative microscopic analysis did not reveal significant alterations in the numbers of Ki-67- and proliferating cell nuclear antigen (PCNA)-positive cells in the hippocampal dentate gyrus (DG) of guanosine-treated mice. However, guanosine treatment resulted in a significant increase in the number of immature neurons, as assessed by immunohistochemistry for the neurogenic differentiation protein. Interestingly, this effect was localized to the ventral hippocampal DG, a functionally distinct region of this structure known to regulate emotional and motivational behaviours. Taken together, our results suggest that the antidepressant-like effect of chronic guanosine treatment is associated with an increase in neuronal differentiation, reinforcing the notion that this nucleoside may be an endogenous mood modulator.

There is growing awareness that repeated mild traumatic brain injury (r-mTBI) can cause deficits in learning and memory performance, however there is still a paucity of preclinical data identifying the extent of these deficits. Epidemiological data shows that juveniles are at high risk to sustain r-mTBI, and these injuries may cause significant changes in cognitive abilities, as they occur during a period where the brain is still maturing. This is particularly true for the hippocampus, a brain region important for learning and memory processes. R-mTBI during the juvenile period may disrupt functional capacity of the hippocampus, and thus the normal development of cognitive processes associated with this structure. To examine this issue we used a model of awake closed head injury (ACHI) and administered 8 impacts over a 4 day period to juvenile male and female rats (P25-28). A neurological assessment was preformed after each impact, and anxiety and learning related behaviours were examined 1 and 7 days after the last impact. Our results indicate that r-mTBI was associated with sensorimotor deficits in the acute phase immediately after each procedure. R-mTBI also reduced the capacity for hippocampal-dependent learning for at least 7 days post-injury, but did not result in any long-lasting changes in anxiety-related behaviours.

In this review, the benefits of physical exercise on structural and functional plasticity in the hippocampus are discussed. The evidence is clear that voluntary exercise in rats and mice can lead to increases in hippocampal neurogenesis and enhanced synaptic plasticity which ultimately result in improved performance in hippocampal-dependent tasks. Furthermore, in models of neurological disorders, including fetal alcohol spectrum disorders, traumatic brain injury, stroke, and neurodegenerative disorders including Alzheimer’s, Parkinson’s and Huntington’s disease exercise can also elicit beneficial effects on hippocampal function. Ultimately this review highlights the multiple benefits of exercise on hippocampal function in both the healthy and the diseased brain.

The rodent hippocampus is a large and complex bilateral structure lying directly beneath the cortex. It has often been described as resembling a set of “ram’s horns” denoting the fact that it projects from a midline or septal point and extends outward (temporal) and downward (ventral) as you move rostral toward the temporal pole. Perhaps not surprisingly, the dorsal (septal), middle (intermediate), and ventral (temporal) portions of this structure appear to subserve different cognitive and limbic functions, thus researchers are likely to vary in which portion of the structure they wish to record from. The purpose of this chapter is to provide those with a desire to conduct in vivo electrophysiology with the practical knowledge they will need to conduct such investigations. We focus on stimulating the medial perforant pathway and recording from the hilus of the dentate gyrus along the dorsoventral extent of the hippocampal formation.

Fragile X Syndrome (FXS) is the most common inherited cause of intellectual disability, and is the leading known single-gene cause of autism spectrum disorder. FXS patients display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently there is no cure for this condition, however minocycline is becoming commonly prescribed as a treatment for FXS patients. Minocycline has been reported to alleviate social behavioural deficits, and improve verbal functioning in patients with FXS; however, its mode of action is not well understood. Previously we have shown that FXS results in learning impairments that involve deficits in N-methyl-d-aspartate (NMDA) receptor-dependent synaptic plasticity in the hippocampal dentate gyrus (DG). Here we tested whether chronic treatment with minocycline can improve these deficits by enhancing NMDA receptor-dependent functional and structural plasticity in the DG. Minocycline treatment resulted in a significant enhancement in NMDA receptor function in the dentate granule cells. This was accompanied by an increase in PSD-95 and GluN2A and GluN2B subunits in hippocampal synaptoneurosome fractions. Minocycline treatment also enhanced dentate granule cell dendritic length and branching. In addition, our results show that chronic minocycline treatment can rescue performance in novel object recognition in FXS mice. These findings indicate that minocycline treatment has both structural and functional benefits for hippocampal cells, which may partly contribute to the pro-cognitive effects minocycline appears to have for treating FXS.

Exposure to ethanol in utero is associated with a myriad of sequelae for the offspring. Some of these effects are morphological in nature and noticeable from birth, while others involve more subtle changes to the brain that only become apparent later in life when the individuals are challenged cognitively. One brain structure that shows both functional and structural deficits following prenatal ethanol exposure is the hippocampus. The hippocampus is composed of two interlocking gyri, the cornu ammonis (CA) and the dentate gyrus (DG), and they are differentially affected by prenatal ethanol exposure. The CA shows a more consistent loss in neuronal numbers, with different ethanol exposure paradigms, than the DG, which in contrast shows more pronounced and consistent deficits in synaptic plasticity. In this study we show that significant deficits in adult hippocampal neurogenesis are apparent in aged animals following prenatal ethanol exposure. Deficits in hippocampal neurogenesis were not apparent in younger animals. Surprisingly, even when ethanol exposure occurred in conjunction with maternal stress, deficits in neurogenesis did not occur at this young age, suggesting that the capacity for neurogenesis is highly conserved early in life. These findings are unique in that they demonstrate for the first time that deficits in neurogenesis associated with prenatal ethanol consumption appear later in life.

Alcohol consumption during pregnancy is deleterious to the developing brain of the fetus and leads to persistent deficits in adulthood. Long-term potentiation (LTP) is a biological model for learn- ing and memory processes and previous evidence has shown that prena- tal ethanol exposure (PNEE) affects LTP in a sex specific manner during adolescence. The objective of this study was to determine if there are sex specific differences in adult animals and to elucidate the underlying molecular mechanisms that contribute to these differences. Pregnant Sprague-Dawley dams were assigned to either; liquid ethanol, pair-fed or standard chow diet. In vivo electrophysiology was performed in the hippocampal dentate gyrus (DG) of adult offspring. LTP was induced by administering 400 Hz stimuli. Western blot analysis for glutamine syn- thetase (GS) and glutamate decarboxylase from tissue of the DG indi- cated that GS expression was increased following PNEE. Surprisingly, adult females did not show any deficit in N-methyl-D-aspartate (NMDA)-dependent LTP after PNEE. In contrast, males showed a 40% reduction in LTP. It was indicated that glutamine synthetase expression was increased in PNEE females, suggesting that altered excitatory neuro- transmitter replenishment may serve as a compensatory mechanism. Ovariectomizing females did not influence LTP in control or PNEE ani- mals, suggesting that circulating estradiol levels do not play a major role in maintaining LTP levels in PNEE females. These results demon- strate the sexually dimorphic effects of PNEE on the ability for the adult brain to elicit LTP in the DG. The mechanisms for these effects are not fully understood, but an increase in glutamine synthetase in females may underlie this phenomenon. V C 2013 Wiley Period- icals, Inc.

Fetal alcohol spectrum disorders occur when a mother drinks during pregnancy and can greatly influence synaptic plasticity and cognition in the offspring. In this study we determined whether there are periods during brain development that are more susceptible to the effects of ethanol exposure on hippocampal synaptic plasticity. In particular, we evaluated how the ability to elicit long-term potentiation (LTP) in the hippocampal dentate gyrus (DG) was affected in young adult rats that were exposed to ethanol during either the 1st, 2nd, or 3rd trimester equivalent. As expected, the effects of ethanol on young adult DG LTP were less severe when exposure was limited to a particular trimester equivalent when compared to exposure throughout gestation. In males, ethanol exposure during the 1st, 2nd or 3rd trimester equivalent did not significantly reduce LTP in the DG. In females, ethanol exposure during either the 1st or 2nd trimester equivalents did not impact LTP in early adulthood, but following exposure during the 3rd trimester equivalent alone, LTP was significantly increased in the female DG. These results further exemplify the disparate effects between the ability to elicit LTP in the male and female brain following perinatal ethanol exposure (PNEE).

Fragile-X syndrome (FXS) is caused by the transcriptional repression of the Fmr1 gene resulting in loss of the Fragile-X mental retardation protein (FMRP). This leads to cognitive impairment in both male and female patients, however few studies have focused on the impact of FXS in females. Significant cognitive impairment has been reported in approximately 35% of women who exhibit a heterozygous Fmr1 gene mutation, however to date there is a paucity of information regarding the mechanistic underpinnings of these deficits. We, and others, have recently reported that there is significant impairment in N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) in the hippocampal dentate gyrus (DG) of male Fmr1 knock out mice. Here we examined if female mice displaying a heterozygous loss of the Fmr1 gene (Fmr1+/‐) would exhibit similar impairments in DG-dependent spatial memory processing and NMDAR hypofunction. We found that Female Fmr1+/‐ mice did not show impaired metabotropic glutamate receptor (mGluR)-LTD in the CA1 region, and could perform well on a temporal ordering task that is thought to involve this brain region. In contrast, female Fmr1+/‐ mice showed impairments in a pattern separation task thought to involve the DG, and also displayed a significant impairment in both NMDAR-dependent LTD and LTP in this region. The LTP impairment could be rescued by administering the NMDAR co-agonist, glycine. Our data suggests that NMDAR hypofunction in the DG may partly contribute to learning and memory impairment in female Fmr1+/‐ mice. Targeting NMDAR-dependent mechanisms may offer hope as a new therapeutic approach for treating female FXS patients with learning and memory impairments.

Background The consumption of alcohol during pregnancy can result in abnormal fetal development and impaired brain function in humans and experimental animal models. Depending on the pattern of consumption, the dose, and the period of exposure to ethanol (EtOH), a variety of structural and functional brain deficits can be observed. Methods This study compared the effects of EtOH exposure during distinct periods of brain development on oxidative damage and endogenous antioxidant status in various brain regions of adult female and male Sprague Dawley rats. Pregnant dams and neonatal rats were exposed to EtOH during one of the following time windows: between gestational days (GDs) 1 and 10 (first trimester equivalent); between GDs 11 and 21 (second trimester equivalent); or between postnatal days (PNDs) 4 and 10 (third trimester equivalent). Results EtOH exposure during any of the 3 trimester equivalents significantly increased lipid peroxidation in both the cornus ammonis (CA) and dentate gyrus (DG) subregions of the hippocampus, while also decreasing the levels of the endogenous antioxidant glutathione in the hippocampal CA and DG subregions as well as the prefrontal cortex of young adult animals (PND 60). Conclusions These results indicate that EtOH exposure during restricted periods of brain development can have long-term consequences in the adult brain by dysregulating its redox status. This dysfunction may underlie, at least in part, the long-term alterations in brain function associated with fetal alcohol spectrum disorders.

Adult hippocampal neurogenesis can be modulated by various physiological and pathological conditions, including stress, affective disorders, and several neurological conditions. Given the proposed role of this form of structural plasticity in the functioning of the hippocampus (namely learning and memory and affective behaviors), it is believed that alterations in hippocampal neurogenesis might underlie some of the behavioral deficits associated with these psychiatric and neurological conditions. Thus, the search for compounds that can reverse these deficits with minimal side effects has become a recognized priority. In the present study we tested the pro-neurogenic effects of isoxazole 9 (Isx-9), a small synthetic molecule that has been recently identified through the screening of chemical libraries in stem cell-based assays. We found that administration of Isx-9 for 14days was able to potentiate cell proliferation and increase the number of immature neurons in the hippocampal DG of adult rats. In addition, Isx-9 treatment was able to completely reverse the marked reduction in these initial stages of the neurogenic process observed in vehicle-treated animals (which were submitted to repeated handling and exposure to daily intraperitoneal injections). Based on these results, we recommend that future neurogenesis studies that require repeated handling and manipulation of animals should include a naive (non-manipulated) control to determine the baseline levels of hippocampal cell proliferation and neuronal differentiation. Overall, these findings demonstrate that Isx-9 is a promising synthetic compound for the mitigation of stress-induced deficits in adult hippocampal neurogenesis. Future studies are thus warranted to evaluate the pro-neurogenic properties of Isx-9 in animal models of affective and neurological disorders associated with impaired hippocampal structural plasticity.

Alcohol consumption during pregnancy can result in a myriad of health problems in the affected offspring ranging from growth deficiencies to central nervous system impairments that result in cognitive deficits. Adult hippocampal neurogenesis is thought to play a role in cognition (i.e. learning and memory) and can be modulated by extrinsic factors such as alcohol consumption and physical exercise. We examined the impact of voluntary physical exercise on adult hippocampal neurogenesis in a rat model of fetal alcohol spectrum disorders (FASD). Intragastric intubation was used to deliver ethanol to rats in a highly controlled fashion through all three trimester equivalents (i.e. throughout gestation and during the first 10 days of postnatal life). Ethanol-exposed animals and their pair-fed and ad libitum controls were left undisturbed until they reached a young adult stage at which point they had free access to a running wheel for 12 days. Prenatal and early postnatal ethanol exposure altered cell proliferation in young adult female rats and increased early neuronal maturation without affecting cell survival in the dentate gyrus (DG) of the hippocampus. Voluntary wheel running increased cell proliferation, neuronal maturation and cell survival as well as levels of brain-derived neurotrophic factor in the DG of both ethanol-exposed female rats and their pair-fed and ad libitum controls. These results indicate that the capacity of the brain to respond to exercise is not impaired in this model of FASD, highlighting the potential therapeutic value of physical exercise for this developmental disorder.

Exposure to ethanol during pregnancy can be devastating to the developing nervous system, leading to significant central nervous system dysfunction. The hippocampus, one of the two brain regions where neurogenesis persists into adulthood, is particularly sensitive to the teratogenic effects of ethanol. In the present study, we tested a rat model of fetal alcohol syndrome (FAS) with ethanol administered via gavage throughout all three trimester equivalents. Subsequently, we assessed cell proliferation, as well as neuronal survival, and differentiation in the dentate gyrus of the hippocampus of adolescent (35 days old), young adult (60 days old) and adult (90 days old) Sprague-Dawley rats. Using both extrinsic (bromodeoxyuridine) and intrinsic (Ki-67) markers, we observed no significant alterations in cell proliferation and survival in ethanol-exposed animals when compared with their pair-fed and ad libitum controls. However, we detected a significant increase in the number of new immature neurons in animals that were exposed to ethanol throughout all three trimester equivalents. This result might reflect a compensatory mechanism to counteract the deleterious effects of prenatal ethanol exposure or an ethanol-induced arrest of the neurogenic process at the early neuronal maturation stages. Taken together these results indicate that exposure to ethanol during the period of brain development causes a long-lasting dysregulation of the neurogenic process, a mechanism that might contribute, at least in part, to the hippocampal deficits that have been reported in rodent models of FAS.

Perturbations in neurogenesis in the adult brain have been implicated in impaired learning and memory. In the present study, we investigated which stages of the neurogenic process are affected in the transgenic YAC128 mouse model of Huntington disease (HD). Hippocampal neuronal proliferation was altered in the dentate gyrus (DG) of YAC128 mice as compared with wild-type (WT) littermate controls in early symptomatic to end-stage mice. In addition, we detected a significantly lower number of immature neurons in the DG of young, pre-symptomatic YAC128 mice. This decrease in neuronal differentiation persisted through the progression of the disease, and resulted in an overall reduction in the number of new mature neurons in the DG of YAC128 mice. There were no changes in cell proliferation and differentiation in the subventricular zone (SVZ). In this study, we demonstrate decreases in neurogenesis in the DG of YAC128 mice, and these deficits may contribute to the cognitive abnormalities observed in these animals.

Prenatal ethanol exposure is invariably detrimental to the developing central nervous system and the hippocampus is particularly sensitive to the teratogenic effects of ethanol. Prenatal ethanol exposure has been shown to result in hippocampal cell loss, altered neuronal morphology and impaired performance on hippocampal-dependent learning and memory tasks in rodents. The dentate gyrus (DG) of the hippocampus is one of the few brain regions where neurogenesis continues into adulthood. This process appears to have functional significance and these newly generated neurons are believed to play important functions in learning and memory. Recently, several groups have shown that adult hippocampal neurogenesis is compromised in animal models of fetal alcohol spectrum disorders (FASD). The direction and magnitude of any changes in neurogenesis, however, appear to depend on a variety of factors that include: the rodent model used; the blood alcohol concentration achieved; the developmental time point when alcohol was administered; and the frequency of ethanol exposure. In this review we will provide an overview of the different rodent models of FASD that are commonly used in this research, emphasizing each of their strengths and limitations. We will also present an up-to-date summary on the effects of prenatal/neonatal ethanol exposure on adult hippocampal neurogenesis and cell loss, highlighting some of the possible molecular mechanisms that might be involved.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the selective loss of the expression of the Fmr1 gene. Key symptoms in FXS include intellectual impairment and abnormal anxiety-related behaviors. Fmr1 knockout (KO) mice exhibited reduced anxiety on two behavioral tests as well as a blunted corticosterone response to acute stress. Spatial learning and memory was not impaired when tested with both the classic Morris water and Plus-shaped mazes. Adult hippocampal neurogenesis has been associated with spatial learning and memory and emotions such as anxiety and depression. The process of neurogenesis appears abnormal in young adult Fmr1 KO mice, with significantly fewer bromodeoxyuridine-positive cells surviving for at least 4 weeks in the ventral subregion of the dentate gyrus (DG), a hippocampal subregion more closely associated with emotion than the dorsal DG. Within this smaller pool of surviving cells, we observed a concomitant increase in the proportion of surviving cells that acquire a neuronal phenotype. We did not observe a clear difference in cell proliferation using both endogenous and exogenous markers. This work indicates that loss of Fmr1 expression can alter anxiety-related behaviors in mice as well as produce region-specific alterations in hippocampal adult neurogenesis.

The consumption of alcohol during gestation is detrimental to the developing central nervous system (CNS). The severity of structural and functional brain alterations associated with alcohol intake depends on many factors including the timing and duration of alcohol consumption. The hippocampal formation, a brain region implicated in learning and memory, is highly susceptible to the effects of developmental alcohol exposure. Some of the observed effects of alcohol on learning and memory may be due to changes at the synaptic level, as this teratogen has been repeatedly shown to interfere with hippocampal synaptic plasticity. At the molecular level alcohol interferes with receptor proteins and can disrupt hormones that are important for neuronal signaling and synaptic plasticity. In this review we examine the consequences of prenatal and early postnatal alcohol exposure on hippocampal synaptic plasticity and highlight the numerous factors that can modulate the effects of alcohol. We also discuss some potential mechanisms responsible for these changes as well as emerging therapeutic avenues that are beginning to be explored.

Prenatal ethanol exposure (PNEE) causes significant deficits in functional (i.e., synaptic) plasticity in the dentate gyrus (DG) and cornu ammonis (CA) hippocampal sub-regions of young adult male rats. Previous research has shown that in the DG, these deficits are not apparent in age-matched PNEE females. This study aimed to expand these findings and determine if PNEE induces deficits in hippocampal-dependent behaviours in both male and female young adult rats (PND 60). The metric change behavioural test examines DG-dependent deficits by determining whether an animal can detect a metric change between two identical objects. The temporal order behavioural test is thought to rely in part on the CA sub-region of the hippocampus and determines whether an animal will spend more time exploring an object that it has not seen for a larger temporal window as compared to an object that it has seen more recently. Using the liquid diet model of FASD (where 6.6% (v/v) ethanol is provided through a liquid diet consumed ad libitum throughout the entire gestation), we found that PNEE causes a significant impairment in the temporal order task, while no deficits in the DG-dependent metric change task were observed. There were no significant differences between males and females for either task. These results indicate that behaviours relying partially on the CA-region may be more affected by PNEE than those that rely on the DG.

The spontaneous or targeted deletion of the nuclear receptor transcription factor Nr2e1 produces a mouse that shows hypoplasia of the hippocampal formation and reduced neurogenesis in adult mice. In these studies we show that hippocampal synaptic transmission appears normal in the dentate gyrus and cornu ammonis 1 subfields of adult mice that lack Nr2e1 (Nr2e1-/-), and that fEPSP shape, paired-pulse responses, and short-term plasticity are not substantially altered in either subfield. In contrast, the expression of long-term potentiation is selectively impaired in the dentate gyrus, and not in the cornu ammonis 1 subfield. Golgi analysis revealed that there was a significant reduction in both dendritic branching and dendritic length that was specific to dentate gyrus granule cells in the Nr2e1-/- mice. These results indicate that Nr2e1 deletion can significantly alter both synaptic plasticity and dendritic structure in the dentate gyrus.

Voluntary exercise produces a dramatic increase in the number of bromodeoxyuridine (BrdU)-positive cells in the adult dentate gyrus (DG); however, it has never been determined whether this increase reflects neurogenic activity or some exercise-induced change in the metabolic processing of systemically injected BrdU. In these experiments, we show that 1) 200 mg/kg is a saturating dose for single injections of BrdU in both control and voluntary exercise animals; 2) there is significantly more cell labeling in animals that exercise when saturating doses of BrdU are employed; 3) high doses of BrdU do not affect the number, appearance, or distribution of labeled cells; 4) voluntary exercise leads to similar increases in the number of cells expressing Ki67, an intrinsic marker of cellular proliferation; 5) both dendritic length and complexity are significantly increased in the DG of animals that exercise; and 6) spine density is significantly greater on dendrites in the DG following voluntary exercise. This study demonstrates that exercise up-regulates neurogenic activity in the DG of adult rats, independently of any putative changes in altered BrdU metabolism, and that it also substantially alters the morphology of dentate granule cell dendrites. The dramatic changes in the cytoarchitecture of the DG induced by voluntary exercise might underlie the enhancement of hippocampal long-term potentiation and hippocampal-dependent memory that our group has previously described. These results suggest that exercise may be an effective component of therapeutic regimes aimed at improving the functioning of individuals with neuropathologies that involve the degradation of cells in the hippocampus. J. Comp. Neurol. 486:39–47, 2005. © 2005 Wiley-Liss, Inc.

Adiponectin (ADN) is an adipocyte-secreted protein with insulin-sensitizing, antidiabetic, antiinflammatory, and antiatherogenic properties. Evidence is also accumulating that ADN has neuroprotective activities, yet the underlying mechanism remains elusive. Here we show that ADN could pass through the blood-brain barrier, and elevating its levels in the brain increased cell proliferation and decreased depression-like behaviors. ADN deficiency did not reduce the basal hippocampal neurogenesis or neuronal differentiation but diminished the effectiveness of exercise in increasing hippocampal neurogenesis. Furthermore, exercise-induced reduction in depression-like behaviors was abrogated in ADN-deficient mice, and this impairment in ADN-deficient mice was accompanied by defective running-induced phosphorylation of AMP-activated protein kinase (AMPK) in the hippocampal tissue. In vitro analyses indicated that ADN itself could increase cell proliferation of both hippocampal progenitor cells and Neuro2a neuroblastoma cells. The neurogenic effects of ADN were mediated by the ADN receptor 1 (ADNR1), because siRNA targeting ADNR1, but not ADNR2, inhibited the capacity of ADN to enhance cell proliferation. These data suggest that adiponectin may play a significant role in mediating the effects of exercise on hippocampal neurogenesis and depression, possibly by activation of the ADNR1/AMPK signaling pathways, and also raise the possibility that adiponectin and its agonists may represent a promising therapeutic treatment for depression., link_to_OA_fulltext

We have previously shown that voluntary running acts as an anxiolytic and ameliorates deficits in hippocampal neurogenesis and spatial learning. It also reduces depression-like behaviors that are normally observed in rats that were administered either low (30 mg/kg) or moderate (40 mg/kg) doses of corticosterone (CORT). However, the protective effects of running were absent in rats treated with a high (50 mg/kg) dose of CORT. We examined whether allowing animals to exercise for 2 weeks prior and/or concurrently with the administration of 50 mg/kg CORT treatment could have similar protective effects. We examined hippocampal neurogenesis using immuno-histochemical staining of proliferative and survival cells with the thymidine analogs (BrdU, CIdU, and IdU). In addition, we monitored synaptic protein expression and quantified the levels of neurotrophic factors in these animals as well as performing behavioral analyses (forced swim test and sucrose preference test). Our results indicate that the depressive phenotype and reductions in neurogenesis that normally accompany high CORT administration could only be prevented by allowing animals to exercise both prior to and concurrently with the CORT administration period. These animals also showed increases in both synaptophysin and PSD-95 protein levels, but surprisingly, neither brain-derived neurotrophic factor (BDNF) nor insulin-like growth factor 1 (IGF-1) levels were increased in these animals. The results suggest that persistent exercise can strengthen resilience to stress by promoting hippocampal neurogenesis and increasing synaptic protein levels, thereby reducing the deleterious effects of stress.

Huntington's disease (HD) is a progressive and fatal neurodegenerative disorder caused by a polyglutamine expansion in the gene encoding the protein huntingtin. The disease progresses over decades, but often patients develop cognitive impairments that precede the onset of the classical motor symptoms. Similar to the disease progression in humans, the yeast artificial chromosome (YAC) 128 HD mouse model also exhibits cognitive dysfunction that precedes the onset of the neuropathological and motor impairments characteristic of HD. Thus, the purpose of this study was to evaluate whether short- and long-term synaptic plasticity in the hippocampus, two related biological models of learning and memory processes, were altered in YAC128 mice in early stages of disease progression. We show that the YAC128 hippocampal dentate gyrus (DG) displays marked reductions in paired-pulse depression both at 3 and 6 months of age. In addition, significantly enhanced post-tetanic and short-term potentiation are apparent in YAC128 mice after high-frequency stimulation at this time. Early and late forms of long-term plasticity were not altered at this stage. Together these findings indicate that there may be elevated neurotransmitter release in response to synaptic stimulation in YAC128 mice during the initial phase of disease progression. These abnormalities in short-term plasticity detected at this stage in YAC128 HD transgenic mice indicate that aberrant information processing at the level of the synapses may contribute, at least in part, to the early onset of cognitive deficits that are characteristic of this devastating neurodegenerative disorder.

Cumulative evidence has indicated that there is an important role for adult hippocampal neurogenesis in cognitive function. With the increasing prevalence of cognitive decline associated with neurodegenerative diseases among the ageing population, physical exercise, a potent enhancer of adult hippocampal neurogenesis, has emerged as a potential preventative strategy/treatment to reduce cognitive decline. Here we review the functional role of adult hippocampal neurogenesis in learning and memory, and how this form of structural plasticity is altered in neurodegenerative diseases known to involve cognitive impairment. We further discuss how physical exercise may contribute to cognitive improvement in the ageing brain by preserving adult neurogenesis, and review the recent approaches for measuring changes in neurogenesis in the live human brain.

It is known that NMDA receptors can modulate adult hippocampal neurogenesis, but the contribution of specific regulatory GluN2 subunits has been difficult to determine. Here we demonstrate that mice lacking GluN2A (formerly NR2A) do not show altered cell proliferation or neuronal differentiation, but present significant changes in neuronal morphology in dentate granule cells. Specifically, GluN2A deletion significantly decreased total dendritic length and dendritic complexity in DG neurons located in the inner granular zone. Furthermore, the absence of GluN2A also resulted in a localized increase in spine density in the middle molecular layer, a region innervated by the medial perforant path. Interestingly, alterations in dendritic morphology and spine density were never seen in dentate granule cells located in the outer granular zone, a region that has been hypothesized to contain older, more mature, neurons. These results indicate that although the GluN2A subunit is not critical for the cell proliferation and differentiation stages of the neurogenic process, it does appear to play a role in establishing synaptic and dendritic morphology in maturing dentate granule cells localized in the inner granular zone.

Long-term potentiation (LTP) of synaptic efficacy was exam- ined in interneurons and giant cells in the stratum radiatum region of the hippocampal CA1 subfield. Cells were visually selected using differential interference contrast (DIC) optics and filled with biocytin while being re- corded using whole-cell patch-clamp techniques. Electrophysiological crite- ria, including spike height, width, and degree of spike adaptation shown to sustained depolarization, proved inadequate for differentiating interneurons from giant cells. We found that cells in the stratum radiatum, however, could be reliably differentiated using DIC optics or following intracellular staining. The response of the two cell types to tetanic stimulation further dissociated them. Long-term potentiation, dependent on the activation of NMDAr (N- methyl-D-aspartate receptors), could reliably be induced in interneurons with stimuli administered at 200 Hz, but not 100 Hz. Giant cells, in contrast, exhibited NMDA receptor-dependent LTP in response to 100-Hz stimuli, but not the 200-Hz stimuli. LTP induction in interneurons also appeared temper- ature-dependent, being much more robust at 34°C than at room tempera- ture. The LTP in both cell types required postsynaptic calcium influx, and was not due to the passive propagation of LTP induction in neighboring pyramidal cells. These results suggest that different cell types within the hippocampal formation may preferentially alter synaptic connectivity in a frequency- specific manner. Hippocampus 2000;10:673-683. © 2000 Wiley-Liss, Inc.

The hippocampus plays a crucial role in the formation of spatial memories, and it is thought that adult hippocampal neurogenesis may participate in this form of learning. To better elucidate the relationship between neurogenesis and spatial learning, we examined both across the entire life span of mice. We found that cell proliferation, neuronal differentiation, and neurogenesis significantly decrease with age, and that there is an abrupt reduction in these processes early on, between 1.5-3 months of age. After this, the neurogenic capacity continues to decline steadily. The initial abrupt decline in adult neurogenesis was paralleled by a significant reduction in Morris Water Maze performance, however overall learning and memory remained constant thereafter. Further analysis of the search strategies employed revealed that reductions in neurogenesis in the aging brain were strongly correlated with the adoption of spatially imprecise search strategies. Overall, performance measures of learning and memory in the Morris Water Maze were maintained at relatively constant levels in aging animals due to an increase in the use of spatially imprecise search strategies.

The medial perforant path (MPP) and lateral perforant path (LPP) inputs to the hippocampal dentate gyrus form two distinct laminar inputs onto the middle and distal aspects of granule cell dendrites. Previous evidence indicated that paired stimuli reliably produced paired-pulse depression (PPD) in the MPP and paired-pulse facilitation (PPF) in the LPP. Despite this, several years of practical experience in our laboratory questioned the utility of using paired-pulse administration to reliably differentiate the MPP and LPP in vitro. Using visualized field and whole-cell recordings in male Sprague-Dawley rats, we demonstrate that both pathways show net PPF of the excitatory postsynaptic potential (fEPSP) at 50-ms interpulse intervals. LPP afferents did reliably exhibit greater PPF than MPP afferents. Thus, the LPP reliably exhibits a greater paired-pulse ratio than the MPP. The magnitude of the paired-pulse ratio was reduced in both afferents by raising calcium levels or lowering the temperature of the recording chamber. PPD of MPP-evoked fEPSPs was only reliably detected at moderate to high stimulus intensities when population spike activity was evident. PPD was more evident in whole cell voltage clamp recordings but nonetheless was not completely diagnostic as PPD was occasionally observed with LPP stimulation as well. We found the MPP and LPP could be reliably identified using conventional microscopy with hippocampal slices, and that they could be distinguished through the analysis of evoked waveform kinetics. This work refines our knowledge of electrophysiological differences between MPP and LPP projections and will help to facilitate the selective activation of these pathways.

1. Whole cell recordings and high-speed fluorescence imaging were used to investigate the contribution of voltage-gated Ca2+ channels to the resting Ca2+ concentration ([Ca2+]i) in hippocampal CA1 pyramidal neurons. 2. Prolonged membrane hyperpolarization produced, in a voltage-dependent manner, sustained decreases in [Ca2+]i in the somatic and apical dendritic regions of the neuron. This hyperpolarization-induced decrease in [Ca2+]i occurred with a time constant of approximately 1 s and was maintained for as long as the membrane potential was held at the new level. Ratiometric measures showed that [Ca2+]i is significantly elevated at holding potentials of -50 mV compared with -80 mV. 3. The hyperpolarization-induced decrease in [Ca2+]i was reduced significantly by 200 microM Cd2+ and 10 microM nimodipine, but was only slightly inhibited by 50 microM Ni2+. The largest amplitude decrease in [Ca2+]i was observed in the proximal apical dendrites with the amplitude of the Ca2+ change decreasing with further distance from the soma. 4. Whole cell recordings from acutely isolated hippocampal pyramidal neurons reveal a slowly inactivating Ca2+ current with similar voltage dependence and pharmacology to the hyperpolarization-induced decrease in [Ca2+]i. 5. The data suggest that a population of dihydropyridine-sensitive Ca2+ channels are active at resting membrane potentials and that this channel activation significantly contributes to the resting [Ca2+]i. These channels appear to be present throughout the neuron and may be located most densely in the proximal apical dendrites.

The authors examine the potential role of the different sources of dendritic Ca2+ influx in long-term depression (LTD) of synaptic efficacy. Recent data on the location and functional distribution of voltage-gated Ca2+ channels obtained from fluorescence imaging and patch clamp experiments are presented. This is followed by a discussion of the existing evidence for different sources of Ca2+ playing a role in the induction of LTD. The authors conclude that a number of key issues need to be resolved before any conclusions are drawn as to the involvement of any specific route of Ca2+ entry in LTD.

Background Prenatal ethanol (EtOH) exposure results in a spectrum of structural, cognitive, and behavioral abnormalities, collectively termed “fetal alcohol spectrum disorders” (FASDs). The hippocampal formation, an area of the brain strongly linked with learning and memory, is particularly vulnerable to the teratogenic effects of EtOH. Prenatal EtOH exposure can lead to long-lasting impairments in the ability to process spatial information, as well as produce long-lasting deficits in the ability of animals to exhibit long-term potentiation (LTP), a biological model of learning and memory processing. These deficits also have the ability to facilitate EtOH and/or other drug abuse later in life. This study sought to determine prenatal EtOH exposure altered the effects of acute EtOH application on synaptic plasticity. Methods Prenatal EtOH exposure was modeled using a liquid diet where dams were given 1 of 3 diets: (i) a liquid diet containing EtOH (35.5% EtOH-derived calories), (ii) a liquid diet, isocaloric to the EtOH diet, but with maltose–dextrin substituting for the EtOH-derived calories, and (iii) an ad libitum diet of standard rat chow. Extracellular recordings from transverse brain slices (350 μm) prepared from 50- to 70-day-old rats, following prenatal EtOH exposure (gestational day 1 to 21). LTP was examined in the dentate gyrus following acute EtOH exposure (0, 20, or 50 mM) in these slices. Results Prenatal EtOH exposure attenuated LTP in the adult dentate gyrus. In control offspring, acute application of EtOH in adulthood attenuated (20 mM) or blocked (50 mM) LTP. Conversely, the effect of acute EtOH application on LTP was not as pronounced in prenatal EtOH offspring. Conclusions Prenatal EtOH exposure alters the sensitivity of the adult dentate gyrus to acute EtOH application producing a long-lasting tolerance to the inhibitory effects of EtOH. This decreased sensitivity may provide a mechanism promoting the formation of drug-associated memories and help explain the increased likelihood of developing an alcohol dependency often observed in individuals with FASDs.

Ethanol exposure during pregnancy can cause structural and functional changes in the brain that can impair cognitive capacity. The hippocampal formation, an area of the brain strongly linked with learning and memory, is particularly vulnerable to the teratogenic effects of ethanol. In the present experiments we sought to determine if the functional effects of developmental ethanol exposure could be linked to ethanol exposure during any single trimester-equivalent. Ethanol exposure during the 1(st) or 3(rd) trimester-equivalent produced only minor changes in synaptic plasticity in adult offspring. In contrast, ethanol exposure during the 2(nd) trimester equivalent resulted in a pronounced decrease in long-term potentiation, indicating that the timing of exposure influences the severity of the deficit. Together, the results from these experiments demonstrate long-lasting alterations in synaptic plasticity as the result of developmental ethanol exposure and dependent on the timing of exposure. Furthermore, these results allude to neural circuit malfunction within the hippocampal formation, perhaps relating to the learning and memory deficits observed in individuals with fetal alcohol spectrum disorders.

Nerve growth factor (NGF) is produced in the hippocampus throughout life and is retrogradely trafficked to septal cholinergic neurons, providing a potential mechanism for modulating cholinergic inputs and, thereby, hippocampal plasticity. To explore NGF modulation of hippocampal plasticity and function, NGF levels were augmented or blocked in intact adult rats, and subsequentin vivoeffects on cholinergic neurons, hippocampal long-term potentiation (LTP), and learning were examined. NGF augmentation significantly enhanced cholinergic neuronal markers and facilitated induction of hippocampal LTP. Blockade of endogenous NGF significantly reduced hippocampal LTP and impaired retention of spatial memory. These findings reveal an essential role for NGF in regulating biological mechanisms related to plasticity and memory in the intact adult brain.

It has been well-established that cell proliferation and neurogenesis in the adult mouse dentate gyrus (DG) can be regulated by voluntary exercise. Recent evidence has suggested that the effects of voluntary exercise can in turn be influenced by environmental factors that regulate the amount of stress an animal is exposed to. In this study, we use bromodeoxyuridine and proliferating cell nuclear antigen immunohistochemistry to show that voluntary exercise produces a significant increase in cell proliferation in the adult mouse DG in both isolated and socially housed mice. This effect on proliferation translates into an increase in neurogenesis and neuronal branching of new neurons in the mice that exercised. Although social condition did not regulate proliferation in young adult mice, an effect of social housing could be observed in mice exposed to acute restraint stress. Surprisingly, only exercising mice housed in isolated conditions showed an increase in cellular proliferation following restraint stress, whereas socially housed, exercising mice, failed to show a significant increase in proliferation. These findings indicate that social housing may increase the effects of any stressful episodes on hippocampal neurogenesis in the mouse DG.

Acute stress impairs memory retrieval and facilitates the induction of long-term depression (LTD) in the hippocampal CA1 region of the adult rodent brain. However, whether such alterations in synaptic plasticity cause the behavioral effects of stress is not known. Here, we report that two selective inhibitors of the induction or expression of stress-enabled, N -methyl- d -aspartate receptor-dependent hippocampal LTD also block spatial memory retrieval impairments caused by acute stress. Additionally, we demonstrate that facilitating the induction of hippocampal LTD in vivo by blockade of glutamate transport mimics the behavioral effects of acute stress by impairing spatial memory retrieval. Thus, the present study demonstrates that hippocampal LTD is both necessary and sufficient to cause acute stress-induced impairment of spatial memory retrieval and provides a new perspective from which to consider the nature of cognitive deficits in disorders whose symptoms are aggravated by stress.