Long‐lasting modulation of synaptic plasticity in rat hippocampus after early‐life complex febrile seizures

A small fraction of children with febrile seizures appears to develop cognitive impairments. Recent studies in a rat model of hyperthermia‐induced febrile seizures indicate that prolonged febrile seizures early in life have long‐lasting effects on the hippocampus and induce cognitive deficits. However, data on network plasticity and the nature of cognitive deficits are conflicting. We examined three specific measures of hippocampal plasticity in adult rats with a prior history of experimental febrile seizures: (i) activity‐dependent synaptic plasticity (long‐term potentiation and depression) by electrophysiological recordings of Schaffer collateral/commissural‐evoked field excitatory synaptic potentials in CA1 of acute hippocampal slices; (ii) Morris water maze spatial learning and memory; and (iii) hippocampal mossy fiber plasticity by Timm histochemistry and quantification of terminal sprouting in CA3 and the dentate gyrus. We found enhanced hippocampal CA1 long‐term potentiation and reduced long‐term depression but normal spatial learning and memory in adult rats that were subjected to experimental febrile seizures on postnatal day 10. Furthermore, rats with experimental febrile seizures showed modest but significant sprouting of mossy fiber collaterals into the inner molecular layer of the dentate gyrus in adulthood. We conclude that enhanced CA1 long‐term potentiation and mild mossy fiber sprouting occur after experimental febrile seizures, without affecting spatial learning and memory in the Morris water maze. These long‐term functional and structural alterations in hippocampal plasticity are likely to play a role in the enhanced seizure susceptibility in this model of prolonged human febrile seizures but do not correlate with overt cognitive deficits.     

Characterization of dopamine D1 and D2 receptor‐expressing neurons in the mouse hippocampus

The hippocampal formation is part of an anatomical system critically involved in learning and memory. Increasing evidence suggests that dopamine plays an important role in learning and memory as well as in several forms of synaptic plasticity. However, the precise identification of neuronal populations expressing D1 or D2 dopamine receptors within the hippocampus is still lacking. To clarify this issue, we used BAC transgenic mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoter of dopamine D1 or D2 receptors. In Drd1a‐EGFP mice, sparse GFP‐expressing neurons were detected among glutamatergic projecting neurons of the granular layer of the dentate gyrus and GABAergic interneurons located in the hilus. A dense immunofluorescence was observed in the outer and medial part of the molecular layer of the dentate gyrus as well as in the inner part of the molecular layer of CA1 corresponding to the terminals of pyramidal neurons of the entorhinal cortex defining the perforant and the temporo‐ammonic pathway respectively. Finally, scattered D1 receptor‐expressing neurons were also identified as GABAergic interneurons in the CA3/CA1 fields of the hippocampus. In Drd2‐EGFP transgenic mice, GFP was exclusively detected in the glutamatergic mossy cells located in the polymorphic layer of the dentate gyrus. This pattern was confirmed in Drd2‐Cre mice crossed with NLS‐LacZ‐Tau^mGFP:LoxP and RCE:LoxP reporter lines. Our results demonstrate that D1 and D2 receptor‐expressing neurons are strictly segregated in the mouse hippocampus. By clarifying the identity of D1 and D2 receptor‐expressing neurons in the hippocampus, this study establishes a basis for future investigations aiming at elucidating their roles in the hippocampal network. © 2012 Wiley Periodicals, Inc.     

Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro

Rises in corticosteroid levels, e.g. after acute stress, impair synaptic plasticity in the rat hippocampus when compared with the situation where levels are basal, i.e. under rest. We here addressed the question whether basal and raised levels of corticosterone affect synaptic plasticity similarly in animals that experienced chronic stress prior to corticosterone application. To this end, rats were exposed to a 21-day variable stress paradigm. Synaptic plasticity was examined in vitro in the dentate gyrus and CA1 hippocampal region, 24 h after exposure to the last stressor, i.e. when corticosterone levels are basal (low). First we observed that long-term potentiation was greatly impaired in both CA1 and dentate gyrus after 3 weeks of exposure to variable stress, when recorded under conditions where plasma corticosterone levels are low. Second, administration of 100 nm corticosterone in vitro reduced synaptic plasticity in CA1 of control rats, but induced no further impairment of synaptic plasticity in chronically stressed rats. Third, in the dentate gyrus, corticosterone incubation did not affect synaptic plasticity in slices from both control and stressed animals. We conclude that: (i) exposure to chronic variable stress per se reduces synaptic plasticity both in CA1 and dentate gyrus; and (ii) acute rises in corticosterone level induce no additional impairment of synaptic plasticity in the CA1 region of chronically stressed rats. It is tempting to speculate that the stress-induced reduction of hippocampal efficacy provides a cellular substrate for cognitive deficits in hippocampus-dependent learning tasks seen after prolonged exposure to stressful events.     

Genetic ablation of tenascin‐C expression leads to abnormal hippocampal CA1 structure and electrical activity in vivo

Despite evidence that the extracellular matrix glycoprotein tenascin‐C (TNC) is implicated in brain development and plasticity, its roles in the intact adult brain are unknown. Here we report that spontaneous local field potential (LFP) activity in freely moving adult TNC‐deficient mice is abnormal. The power of cortical and hippocampal theta and gamma oscillations was enhanced in comparison to wild‐type mice. The alteration in hippocampal gamma rhythm was subfield specific, such that CA1 gamma was accentuated while dentate gyrus gamma was normal. Similar to LFP, synaptic transmission and plasticity at perforant path synapses in the dentate gyrus were unaffected by the mutation. Morphological analyses revealed a subfield‐specific reduction in the CA1 volume and a reduction in the numbers of somatostatin‐positive interneurons in the hippocampus as potential structural substrates of the observed functional aberrations. These findings indicate a role for tenascin‐C in structural organization of the CA1 hippocampal subfield and in shaping neural activity. © 2009 Wiley‐Liss, Inc.     

Genetic deletion of melanin‐concentrating hormone neurons impairs hippocampal short‐term synaptic plasticity and hippocampal‐dependent forms of short‐term memory

The cognitive role of melanin‐concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero‐lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long‐term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal‐dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long‐term potentiation and depression in the CA1 area of the hippocampus. Post‐tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre‐synaptic forms of short‐term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short‐term memory T‐maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short‐term memory by impairing short‐term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short‐term synaptic plasticity in the hippocampus. © 2015 Wiley Periodicals, Inc.     

Hippocampal serotonin‐1A receptor function in a mouse model of anxiety induced by long‐term voluntary wheel running

We have recently demonstrated that, in C57/Bl6 mice, long‐term voluntary wheel running is anxiogenic, and focal hippocampal irradiation prevents the increase in anxiety‐like behaviors and neurobiological changes in the hippocampus induced by wheel running. Evidence supports a role of hippocampal 5‐HT_1A receptors in anxiety. Therefore, we investigated hippocampal binding and function of 5‐HT_1A receptors in this mouse model of anxiety. Four weeks of voluntary wheel running resulted in hippocampal subregion‐specific changes in 5‐HT_1A receptor binding sites and function, as measured by autoradiography of [³H] 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin binding and agonist‐stimulated binding of [³⁵S]GTPγS to G proteins, respectively. In the dorsal CA1 region, 5‐HT_1A receptor binding and function were not altered by wheel running or irradiation. In the dorsal dentate gyrus and CA2/3 region, 5‐HT_1A receptor function was decreased by not only running but also irradiation. In the ventral pyramidal layer, wheel running resulted in a decrease of 5‐HT_1A receptor function, which was prevented by irradiation. Neither irradiation nor wheel running affected 5‐HT_1A receptors in medial prefrontal cortex or in the dorsal or median raphe nuclei. Our data indicate that downregulation of 5‐HT_1A receptor function in ventral pyramidal layer may play a role in anxiety‐like behavior induced by wheel running. Synapse 67:648–655, 2013. © 2013 Wiley Periodicals, Inc.     

Repetitive noxious neonatal stimuli increases dentate gyrus cell proliferation and hippocampal brain‐derived neurotrophic factor levels

Neonatal noxious stimulation has been proposed to model pain triggered by diagnostic/therapeutic invasive procedures in premature infants. Previous studies have shown that hippocampal neurogenesis rate and the behavioral repertoire of adult rats may be altered by neonatal noxious stimuli. The purpose of this study was to evaluate whether noxious stimulation during neonatal period alters the nociceptive response and dentate gyrus neurogenesis when compared to rats subjected to a single noxious stimulus in late infancy. Plasma corticosterone and hippocampal brain‐derived neurotrophic factor (BDNF) levels were measured. Neurogenesis in the dentate gyrus was evaluated in adolescent rats (postnatal day 40; P40) exposed twice to intra‐plantar injections of Complete Freund's adjuvant (CFA) on P1 and P21 (group P1P21) or P8 and P21 (P8P21) or exposed once on P21 (pubertal). On P21, one subset of animals received 5‐bromo‐2′‐deoxyuridine (BrdU) and was euthanized on P40 for identification of proliferating cells in the dentate gyrus. Another subset was sampled for thermal response or plasma corticosterone measurement and hippocampal BDNF levels. Proliferative cell rate in dentate gyrus was the highest in all re‐exposed groups (P < 0.001), except for P8 females (P8P21F), revealing also a sex difference, where P8P21 males showed higher rate than females (P < 0.001). Stimulated groups took longer than CTL animals to lick the paws (P < 0.001), regardless of the age when the noxious stimulus was applied. Re‐exposed groups had lower corticosterone plasma level (P1P21 M and F, P8P21M) than controls. On the contrary, hippocampal BDNF was increased in males from both re‐exposed groups. These results show that infant noxious stimulation in neonatally previously stimulated rats is related to high proliferation in the DG and this association seems to be modified by the animal's sex. The new generated dentate granule cells in the hippocampus may have a role in the long‐term behavioral responses to neonatal nociceptive stimulation. Noxious stimulation in the neonatal period results in sex‐dependent neurogenic response. © 2013 Wiley Periodicals, Inc.     

Long‐term effects of autoimmune CNS inflammation on adult hippocampal neurogenesis

Neurogenesis is a well‐characterized phenomenon within the dentate gyrus (DG) of the adult hippocampus. Aging and chronic degenerative disorders have been shown to impair hippocampal neurogenesis, but the consequence of chronic inflammation remains controversial. In this study the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis was used to investigate the long‐term effects of T cell–mediated central nervous system inflammation on hippocampal neurogenesis. 5‐Bromodeoxyuridine (BrdU)‐labeled subpopulations of hippocampal cells in EAE and control mice (coexpressing GFAP, doublecortin, NeuN, calretinin, and S100) were quantified at the recovery phase, 21 days after BrdU administration, to estimate alterations on the rate and differentiation pattern of the neurogenesis process. The core features of EAE mice DG are (i) elevated number of newborn (BrdU+) cells indicating vigorous proliferation, which in the long term subsided; (ii) enhanced migration of newborn cells into the granule cell layer; (iii) increased level of immature neuronal markers (including calretinin and doublecortin); (iv) trending decrease in the percentage of newborn mature neurons; and (v) augmented gliogenesis and differentiation of newborn neural precursor cells (NPCs) to mature astrocytes (BrdU+/S100+). Although the inflammatory environment in the brain of EAE mice enhances the proliferation of hippocampal NPCs, in the long term neurogenesis is progressively depleted, giving prominence to gliogenesis. The discrepancy between the high number of immature cells and the low number of mature newborn cells could be the result of a caused defect in the maturation pathway. © 2016 Wiley Periodicals, Inc.     

Reduced tonic inhibition in the dentate gyrus contributes to chronic stress‐induced impairments in learning and memory

It is well established that stress impacts the underlying processes of learning and memory. The effects of stress on memory are thought to involve, at least in part, effects on the hippocampus, which is particularly vulnerable to stress. Chronic stress induces hippocampal alterations, including but not limited to dendritic atrophy and decreased neurogenesis, which are thought to contribute to chronic stress‐induced hippocampal dysfunction and deficits in learning and memory. Changes in synaptic transmission, including changes in GABAergic inhibition, have been documented following chronic stress. Recently, our laboratory demonstrated shifts in E_GABA in CA1 pyramidal neurons following chronic stress, compromising GABAergic transmission and increasing excitability of these neurons. Interestingly, here we demonstrate that these alterations are unique to CA1 pyramidal neurons, since we do not observe shifts in E_GABA following chronic stress in dentate gyrus granule cells. Following chronic stress, there is a decrease in the expression of the GABA_A receptor (GABA_AR) δ subunit and tonic GABAergic inhibition in dentate gyrus granule cells, whereas there is an increase in the phasic component of GABAergic inhibition, evident by an increase in the peak amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). Given the numerous changes observed in the hippocampus following stress, it is difficult to pinpoint the pertinent contributing pathophysiological factors. Here we directly assess the impact of a reduction in tonic GABAergic inhibition of dentate gyrus granule cells on learning and memory using a mouse model with a decrease in GABA_AR δ subunit expression specifically in dentate gyrus granule cells (Gabrd/Pomc mice). Reduced GABA_AR δ subunit expression and function in dentate gyrus granule cells is sufficient to induce deficits in learning and memory. Collectively, these findings suggest that the reduction in GABA_AR δ subunit‐mediated tonic inhibition in dentate gyrus granule cells contributes, at least in part, to deficits in learning and memory associated with chronic stress. These findings have significant implications regarding the pathophysiological mechanisms underlying impairments in learning and memory associated with stress and suggest a role for GABA_AR δ subunit containing receptors in dentate gyrus granule cells. © 2016 Wiley Periodicals, Inc.     

Differential subcellular localization of SK3‐containing channels in the hippocampus

Small‐conductance, Ca²⁺‐activated K⁺ (SK) channels are expressed in the hippocampus where they regulate synaptic responses, plasticity, and learning and memory. To investigate the expression of SK3 (KCNN3) subunits, we determined the developmental profile and subcellular distribution of SK3 in the developing mouse hippocampus using western blots, immunohistochemistry and high‐resolution immunoelectron microscopy. The results showed that SK3 expression increased during postnatal development, and that the localization of SK3 changed from being mainly associated with the endoplasmic reticulum and intracellular sites during the first postnatal week to being progressively concentrated in dendritic spines during later stages. In the adult, SK3 was localized mainly in postsynaptic compartments, both at extrasynaptic sites and along the postsynaptic density of excitatory synapses. Double labelling showed that SK3 co‐localized with SK2 (KCNN2) and with N‐methyl‐D‐aspartate receptors. Finally, quantitative analysis of SK3 density revealed two subcellular distribution patterns in different hippocampal layers, with SK3 being unevenly distributed in CA1 region of the hippocampus pyramidal cells and homogeneously distributed in dentate gyrus granule cells. Our results revealed a complex cell surface distribution of SK3‐containing channels and a distinct developmental program that may influence different hippocampal functions.     

Time‐dependent enhancement of hippocampus‐dependent memory after treatment with memantine: Implications for enhanced hippocampal adult neurogenesis

Adult hippocampal neurogenesis has been suggested to play modulatory roles in learning and memory. Importantly, previous studies have shown that newborn neurons in the adult hippocampus are integrated into the dentate gyrus circuit and are recruited more efficiently into the hippocampal memory trace of mice when they become 3 weeks old. Interestingly, a single high‐dose treatment with the N‐methyl‐d ‐aspartate receptor antagonist memantine (MEM) has been shown to increase hippocampal neurogenesis dramatically by promoting cell proliferation. In the present study, to understand the impact of increased adult neurogenesis on memory performance, we examined the effects of a single treatment of MEM on hippocampus‐dependent memory in mice. Interestingly, mice treated with MEM showed an improvement of hippocampus‐dependent spatial and social recognition memories when they were trained and tested at 3–6 weeks, but not at 3 days or 4 months, after treatment with MEM. Importantly, we observed a significant positive correlation between the scores for spatial memory (probe trial in the Morris water maze task) and the number of young mature neurons (3 weeks old) in MEM‐treated mice, but not saline‐treated mice. We also observed that the young mature neurons generated by treatment with MEM were recruited into the trace of spatial memory similarly to those generated through endogenous neurogenesis. Taken together, our observations suggest that treatment with MEM temporally improves hippocampus‐dependent memory formation and that the newborn neurons increased by treatment with MEM contribute to this improvement when they become 3 weeks old. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Hippocampal long‐term potentiation that is elicited by perforant path stimulation or that occurs in conjunction with spatial learning is tightly controlled by beta‐adrenoreceptors and the locus coeruleus

The noradrenergic system, driven by locus coeruleus (LC) activation, plays a key role in the regulating and directing of changes in hippocampal synaptic efficacy. The LC releases noradrenaline in response to novel experience and LC activation leads to an enhancement of hippocampus‐based learning, and facilitates synaptic plasticity in the form of long‐term depression (LTD) and long‐term potentiation (LTP) that occur in association with spatial learning. The predominant receptor for mediating these effects is the β‐adrenoreceptor. Interestingly, the dependency of synaptic plasticity on this receptor is different in the hippocampal subfields whereby in the CA1 in vivo, LTP, but not LTD requires β‐adrenoreceptor activation, whereas in the mossy fiber synapse LTP and LTD do not depend on this receptor. By contrast, synaptic plasticity that is facilitated by spatial learning is highly dependent on β‐adrenoreceptor activation in both hippocampal subfields. Here, we explored whether LTP induced by perforant‐path (pp) stimulation in vivo or that is facilitated by spatial learning depends on β‐adrenoreceptors. We found that under both LTP conditions, antagonising the receptors disabled the persistence of LTP. β‐adrenoreceptor‐antagonism also prevented spatial learning. Strikingly, activation of the LC before high‐frequency stimulation (HFS) of the pp prevented short‐term potentiation but not LTP, and LC stimulation after pp‐HFS‐induced depotentiation of LTP. This depotentiation was prevented by β‐adrenoreceptor‐antagonism. These data suggest that β‐adrenoreceptor‐activation, resulting from noradrenaline release from the LC during enhanced arousal and learning, comprises a mechanism whereby the duration and degree of LTP is regulated and fine tuned. This may serve to optimize the creation of a spatial memory engram by means of LTP and LTD. This process can be expected to support the special role of the dentate gyrus as a crucial subregional locus for detecting and processing novelty within the hippocampus. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Region‐ and age‐specific patterns of histone acetylation related to spatial and cued learning in the water maze

Epigenetic processes, such as histone acetylation, are critical regulators of learning and memory processes. In the present study, we investigated whether training in either a spatial or a cued water maze task undergoes selective changes of histone H3 and H4 acetylation within the hippocampus and the dorsal striatum of C57BL/6 mice. We also attempted to provide new insights into the relationships between deregulation in histone acetylation and age‐associated memory deficits. In young mice, spatial training increased acetylation of histones H3 and H4 selectively in the dorsal hippocampal CA1 region and the dentate gyrus (DG) whereas cued training significantly enhanced acetylation of both histones selectively in the dorsal striatum. Our data also revealed age‐related differences in histone acetylation within the hippocampus and striatum according to task demands. Specifically, age‐related spatial memory deficits were associated with opposite changes of H3 (increase) and H4 (decrease) acetylation in CA1 and DG. After cued learning, both histone acetylation levels were reduced in the striatum of aged mice compared with corresponding young‐adults but remained well above those of cage‐controls. Collectively, our findings suggest an important role for histone acetylation in regulating the relative contributions of the hippocampus and striatum to learning spatial and cued memory tasks. © 2013 Wiley Periodicals, Inc.     

Involvement of Brain‐Derived Neurotrophic Factor and Neurogenesis in Oestradiol Neuroprotection of the Hippocampus of Hypertensive Rats

The hippocampus of spontaneously hypertensive rats (SHR) and deoxycorticosterone (DOCA)‐salt hypertensive rats shows decreased cell proliferation and astrogliosis as well as a reduced number of hilar cells. These defects are corrected after administration of 17β‐oestradiol (E₂) for 2 weeks. The present work investigated whether E₂ treatment of SHR and of hypertensive DOCA‐salt male rats modulated the expression of brain‐derived neurotrophic factor (BDNF), a neurotrophin involved in hippocampal neurogenesis. The neurogenic response to E₂ was simultaneously determined by counting the number of doublecortin‐immunopositive immature neurones in the subgranular zone of the dentate gyrus. Both hypertensive models showed decreased expression of BDNF mRNA in the granular zone of the dentate gyrus, without changes in CA1 or CA3 pyramidal cell layers, decreased BDNF protein levels in whole hippocampal tissue, low density of doublecortin (DCX)‐positive immature neurones in the subgranule zone and decreased length of DCX+ neurites in the dentate gyrus. After s.c. implantation of a single E₂ pellet for 2 weeks, BDNF mRNA in the dentate gyrus, BDNF protein in whole hippocampus, DCX immunopositive cells and the length of DCX+ neurites were significantly raised in both SHR and DOCA‐salt‐treated rats. These results indicate that: (i) low BDNF expression and deficient neurogenesis distinguished the hippocampus of SHR and DOCA‐salt hypertensive rats and (ii) E₂ was able to normalise these biologically important functions in the hippocampus of hypertensive animals.     

Increased anxiety‐like behavior and selective learning impairments are concomitant to loss of hippocampal interneurons in the presymptomatic SOD1(G93A) ALS mouse model

Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease primarily characterized by motor neuron death, causes damages beyond motor‐related areas. In particular, cognitive impairments and hippocampal damage have been reported in ALS patients. We investigated spatial navigation learning and hippocampal interneurons in a mutant SOD1(G93A) mouse (mSOD1) model of ALS. Behavioral tests were performed by using presymptomatic mSOD1 mice. General motor activity was comparable to that of wild‐type mice in the open‐field test, in which, however mSOD1 exhibited increased anxiety‐like behavior. In the Barnes maze test, mSOD1 mice displayed a delay in learning, outperformed wild‐type mice during the first probe trial, and exhibited impaired long‐term memory. Stereological counts of parvalbumin‐positive interneurons, which are crucial for hippocampal physiology and known to be altered in other central nervous system regions of mSOD1 mice, were also performed. At postnatal day (P) 56, the population of parvalbumin‐positive interneurons in mSOD1 mice was already reduced in CA1 and in CA3, and at P90 the reduction extended to the dentate gyrus. Loss of parvalbumin‐positive hippocampal interneurons occurred mostly during the presymptomatic stage. Western blot analysis showed that hippocampal parvalbumin expression levels were already reduced in mSOD1 mice at P56. The hippocampal alterations in mSOD1 mice could at least partly account for the increased anxiety‐like behavior and deficits in spatial navigation learning. Our study provides evidence for cognitive alterations and damage to the γ‐aminobutyric acid (GABA)ergic system in the hippocampus of murine ALS, thereby revealing selective deficits antecedent to the onset of motor symptoms. J. Comp. Neurol. 523:1622–1638, 2015. © 2015 Wiley Periodicals, Inc.     

Anxiolytic Actions of Exercise in Absence of New Neurons

Physical exercise reduces anxiety‐like behavior in adult mice. The specific mechanisms that mediate this anxiolytic effect are unclear, but adult neurogenesis in the dentate gyrus has been implicated because it is robustly increased by running and has been linked to anxiodepressive‐like behavior. We therefore tested the effects of long‐term wheel running on anxiety‐like behavior in GFAP‐TK (TK) mice, a transgenic strain with complete ablation of adult neurogenesis. Five weeks of running reduced anxiety‐like behavior equally in both TK mice and wild type (WT) control mice on two tests, elevated plus‐maze and novelty‐suppressed feeding. WT and TK mice also had similar patterns of c‐fos expression in the hippocampus following anxiety testing. Following testing on the elevated plus‐maze, running reduced c‐fos expression in the dorsal dentate gyrus and CA3 in both WT and TK mice. Following testing on novelty‐suppressed feeding, running reduced c‐fos expression throughout the dentate gyrus and CA3 in both WT and TK mice. Interestingly, following testing on a less anxiogenic version of novelty‐suppressed feeding, running reduced c‐fos expression only in the dorsal dentate gyrus in both WT and TK mice, supporting earlier suggestions that the dorsal hippocampus is less involved in emotional behavior than the ventral region. These results suggest that although running increases adult neurogenesis, new neurons are not involved in the decreased anxiety‐like behavior or hippocampal activation produced by running. © 2016 Wiley Periodicals, Inc.     

Ras‐GRF2 mediates long‐term potentiation,survival, and response to an enriched environment of newborn neurons in the hippocampus

Hippocampal adult neurogenesis contributes to key functions of the dentate gyrus (DG), including contextual discrimination. This is due, at least in part, to the unique form of plasticity that new neurons display at a specific stage of their development when compared with the surrounding principal neurons. In addition, the contribution that newborn neurons make to dentate function can be enhanced by an increase in their numbers induced by a stimulating environment. However, signaling mechanisms that regulate these properties of newborn neurons are poorly understood. Here, we show that Ras‐GRF2 (GRF2), a calcium‐regulated exchange factor that can activate Ras and Rac GTPases, contributes to both of these properties of newborn neurons. Using Ras‐GRF2 knockout mice and wild‐type mice stereotactically injected with retrovirus containing shRNA against the exchange factor, we demonstrate that GRF2 promotes the survival of newborn neurons of the DG at approximately 1–2 weeks after their birth. GRF2 also controls the distinct form of long‐term potentiation that is characteristic of new neurons of the hippocampus through its effector Erk MAP kinase. Moreover, the enhancement of neuron survival that occurs after mice are exposed to an enriched environment also involves GRF2 function. Consistent with these observations, GRF2 knockout mice display defective contextual discrimination. Overall, these findings indicate that GRF2 regulates both the basal level and environmentally induced increase of newborn neuron survival, as well as in the induction of a distinct form of synaptic plasticity of newborn neurons that contributes to distinct features of hippocampus‐derived learning and memory. © 2014 Wiley Periodicals, Inc.     

Differential contributions of dorsal hippocampal subregions to memory acquisition and retrieval in contextual fear-conditioning

The hippocampus is an essential neural structure in developing contextual memory in a situation in which rapid development of associative learning should occur. We tested a subregion-specific contribution in the hippocampus to memory acquisition and retrieval, using the contextual fear-conditioning paradigm. The current results suggest that all three subregions (i.e., CA3, CA1, and dentate gyrus) of the hippocampus contribute to rapid acquisition of contextual memory in the initial phase of acquisition. The involvement of CA3 seems to be important at the earliest stage of acquisition, presumably for developing instant representation of a context. The role of CA3, however, was minimal in retrieving contextual memory after a long time period (i.e., 24 h), whereas the other subregions (i.e., CA1 and dentate gyrus) were critically involved. The results indicate time-dependent differential contributions of the hippocampal subregions to memory acquisition and retrieval in contextual fear-conditioning.     

Caffeine prevents sleep loss‐induced deficits in long‐term potentiation and related signaling molecules in the dentate gyrus

We have previously reported that caffeine prevented sleep deprivation‐induced impairment of long‐term potentiation (LTP) of area CA1 as well as hippocampus‐dependent learning and memory performance in the radial arm water maze. In this report we examined the impact of long‐term (4‐week) caffeine consumption (0.3 g/L in drinking water) on synaptic plasticity ( Alhaider et al., 2010 ) deficit in the dentate gyrus (DG) area of acutely sleep‐deprived rats. The sleep deprivation and caffeine/sleep deprivation groups were sleep‐deprived for 24 h by using the columns‐in‐water technique. We tested the effect of caffeine and/or sleep deprivation on LTP and measured the basal levels as well as stimulated levels of LTP‐related molecules in the DG. The results showed that chronic caffeine administration prevented the impairment of early‐phase LTP (E‐LTP) in the DG of sleep‐deprived rats. Additionally, chronic caffeine treatment prevented the sleep deprivation‐associated decreases in the basal levels of the phosphorylated calcium/calmodulin‐dependent protein kinase II (P‐CaMKII) and brain derived neurotrophic factor (BDNF) as well as in the stimulated levels of P‐CaMKII in the DG area. The results suggest that chronic use of caffeine prevented anomalous changes in the basal levels of P‐CaMKII and BDNF associated with sleep deprivation and as a result contributes to the revival of LTP in the DG region.     

Methamphetamine‐induced enhancement of hippocampal long‐term potentiation is modulated by NMDA and GABA receptors in the shell–accumbens

Addictive drugs modulate synaptic transmission in the meso‐corticolimbic system by hijacking normal adaptive forms of experience‐dependent synaptic plasticity. Psychostimulants such as METH have been shown to affect hippocampal synaptic plasticity, albeit with a less understood synaptic mechanism. METH is one of the most addictive drugs that elicit long‐term alterations in the synaptic plasticity in brain areas involved in reinforcement learning and reward processing. Dopamine transporter (DAT) is one of the main targets of METH. As a substrate for DAT, METH decreases dopamine uptake and increases dopamine efflux via the transporter in the target brain regions such as nucleus accumbens (NAc) and hippocampus. Due to cross talk between NAc and hippocampus, stimulation of NAc has been shown to alter hippocampal plasticity. In this study, we tested the hypothesis that manipulation of glutamatergic and GABA‐ergic systems in the shell‐NAc modulates METH‐induced enhancement of long term potentiation (LTP) in the hippocampus. Rats treated with METH (four injections of 5 mg/kg) exhibited enhanced LTP as compared to saline‐treated animals. Intra‐NAc infusion of muscimol (GABA receptor agonist) decreased METH‐induced enhancement of dentate gyrus (DG)‐LTP, while infusion of AP5 (NMDA receptor antagonist) prevented METH‐induced enhancement of LTP. These data support the interpretation that reducing NAc activity can ameliorate METH‐induced hippocampal LTP through a hippocampus‐NAc‐VTA circuit loop. Synapse 70:325–335, 2016 . © 2016 Wiley Periodicals, Inc.