Re-cycling Paradigms: Cell Cycle Regulation in Adult Hippocampal Neurogenesis and Implications for Depression

Since adult neurogenesis became a widely accepted phenomenon, much effort has been put in trying to understand the mechanisms involved in its regulation. In addition, the pathophysiology of several neuropsychiatric disorders, such as depression, has been associated with imbalances in adult hippocampal neurogenesis. These imbalances may ultimately reflect alterations at the cell cycle level, as a common mechanism through which intrinsic and extrinsic stimuli interact with the neurogenic niche properties. Thus, the comprehension of these regulatory mechanisms has become of major importance to disclose novel therapeutic targets. In this review, we first present a comprehensive view on the cell cycle components and mechanisms that were identified in the context of the homeostatic adult hippocampal neurogenic niche. Then, we focus on recent work regarding the cell cycle changes and signaling pathways that are responsible for the neurogenesis imbalances observed in neuropathological conditions, with a particular emphasis on depression.     

Hippocampal regulation of aversive memories

For many years, the hippocampal formation has been implicated in the regulation of negative emotion, yet the nature of this link has remained elusive. Recent studies have made important links between the hippocampus and regulation of stress hormones that affect aversive memory. Additional studies have shown that the hippocampus regulates the gating of fear by contextual information. An emerging literature also links the hippocampus to prediction errors during fear learning and extinction. The mechanisms by which the hippocampus regulates negative emotion are clearly complicated, but suggest that interventions aimed at restoring normal hippocampal function may help with disorders of negative affect, such as depression or post-traumatic stress disorder and depression.     

Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity

Cholinergic modulation of hippocampal synaptic plasticity has been studied extensively by applying receptor agonists or blockers; however, the effect of rapid physiological cholinergic stimuli on plasticity is largely unknown. Here, we report that septal cholinergic input, activated either by electrical stimulation or via an optogenetic approach, induced different types of hippocampal Schaffer collateral (SC) to CA1 synaptic plasticity, depending on the timing of cholinergic input relative to the SC input. When the cholinergic input was activated 100 or 10 ms prior to SC stimulation, it resulted in α7 nAChR-dependent long-term potentiation (LTP) or short-term depression, respectively. When the cholinergic stimulation was delayed until 10 ms after the SC stimulation, a muscarinic AChR-dependent LTP was induced. Moreover, these various forms of plasticity were disrupted by Aβ exposure. These results have revealed the remarkable temporal precision of cholinergic functions, providing a novel mechanism for information processing in cholinergic-dependent higher cognitive functions.     

Interplay between hormones and exercise on hippocampal plasticity across the lifespan

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.     

Representation of well-learned information in the monkey hippocampus

In the neocortex, extensive training results in enhanced neuronal selectivity for learned stimuli relative to novel stimuli. This enhanced selectivity has been taken as evidence for learning-related plasticity. Much less is known, in contrast, about the representation of well-learned information in the hippocampus. In this study, we examined the responses of individual hippocampal neurons to well-learned and novel stimuli presented in the context of an associative learning task. There was no difference in the response magnitude or visual response latency of hippocampal neurons to the well-learned and novel stimuli. In contrast, hippocampal neurons responded significantly more selectively to the well-learned stimuli relative to the novel stimuli. These findings show that hippocampal cells, like neocortical cells, show greater selectivity to well-learned stimuli compared to novel stimuli.     

培养海马神经元网络学习模型的构建

对于培养的神经元网络而言,学习是外界刺激与网络响应之间联系建立和调控的过程.为构建合适的神经元网络学习模型,采用闭环低频(1 Hz)成对电极的电刺激模拟认知任务,在多通道微电极阵列系统中对培养的海马神经元网络进行训练,使其发生网络层次上的学习行为.经过训练后,神经元网络在刺激后20～80ms内的早期突触后响应明显增加,响应/刺激比(在闭环训练中,电极上任一阶段连续10次刺激的早期突触后响应的个数/10)增大,响应时延减小,并且响应具有选择性,即表明,神经元网络与外界刺激之间已建立可调控的联系,该可调控联系是通过网络的响应来表现的,建立神经元网络与外界刺激之间的可调控联系即网络层次的学习.     

Decreased Hippocampal Neurogenesis Following Olfactory Bulbectomy is Reversed by Repeated Citalopram Administration

1. Whereas much progress has been made in the treatment of depression, the exact pathogenetic mechanisms of the disorder are still poorly understood. It has been proposed that one possible mechanism could be a decrease in adult hippocampal neurogenesis.2. The olfactory bulbectomy (OB) in rats is widely accepted as an animal model of depression. In the present study, we investigated whether hippocampal neurogenesis is affected by an OB, and whether chronic citalopram, a serotonin selective reuptake inhibitor, counteracts OB-induced impairment of neurogenesis.3. Our study shows that OB decreases proliferation of the neuronal precursors in the dentate gyrus and retards their differentiation into mature granule neurons. In OB rats, repeated administration of citalopram restores reduced proliferative activity and enhances the differentiation of precursors into mature calbindin-positive neurons.4. The obtained data demonstrate that a citalopram-induced increase in neurogenesis in OB rats could be one possible mechanism by which antidepressants alleviate OB-induced depressive-like behavior.     

Adaptation of the repellency response to DEET in Rhodnius prolixus

For many years it has been accepted that DEET interferes with the detection of odours from the host instead of having a repellent effect. However, recent work showed that DEET acts as an odorant molecule and elicits a behavioural response in the absence of other stimuli. Therefore, DEET must promote some phenomenon connected with the stimuli-sensory system interaction, such as a sensory adaptation, where the sensory system regulates its sensitivity to different stimuli intensities during continuous or repetitive exposure. In this work, we studied different aspects of the insect-DEET interaction through behavioural observations. Previous exposure of fifth instar Rhodnius prolixus nymphs to DEET decreased the behavioural response to this repellent. We observed a decrease in repellence after different times of continuous stimulation with DEET in a time-dependent manner. The response to DEET was recovered 10 min after exposure, when insects were continuously stimulated during 5 or 10 min; maximum repellence was recovered 20 min after exposure when insects were stimulated for 20 min. DEET produced a repellent effect when nymphs were exposed only to its vapours. These results suggest that exposure to DEET produces adaptation in R. prolixus nymphs, and that the behavioural response elicited by DEET occurs via olfaction when no other stimuli are present.     

Hippocampal synaptic plasticity and NMDA receptors: a role in information storage?

There has recently been renewed interest in the idea that alterations in synaptic efficacy may be the neural basis of information storage. Particular attention has been focused upon long-term potentiation (LTP), a long-lasting, but experimentally induced synaptic change whose physiological properties point to it being a candidate memory mechanism. However, considerations of storage capacity and the possibility of concomitant activity-dependent synaptic depression make it unlikely that individual learning experiences will give rise to gross changes in field potentials similar to those that occur in LTP, even if learning and LTP utilize common neural mechanisms. One way of investigating the functional significance of LTP is to use selective antagonists of those excitatory amino acid receptors whose activation is essential for its induction. This paper discusses various design requirements for such experiments and reviews work indicating that the N-methyl-D-aspartate receptor antagonist AP5 causes a behaviourally selective learning impairment having certain common features to the behavioural profile seen after hippocampal lesions. Two new studies are described whose results show that AP5 has no effect upon the retrieval of previously established memories, and that the dose-response profile of the impairment of spatial learning occurs across a range of extracellular concentrations in hippocampus for which receptor selectivity exists. These experiments show that activation of NMDA receptors is essential for certain kinds of learning.     

AMPA receptor regulation during synaptic plasticity in hippocampus and neocortex

Discovery of long-term potentiation (LTP) in the dentate gyrus of the rabbit hippocampus by Bliss and L?mo opened up a whole new field to study activity-dependent long-term synaptic modifications in the brain. Since then hippocampal synapses have been a key model system to study the mechanisms of different forms of synaptic plasticity. At least for the postsynaptic forms of LTP and long-term depression (LTD), regulation of AMPA receptors (AMPARs) has emerged as a key mechanism. While many of the synaptic plasticity mechanisms uncovered in at the hippocampal synapses apply to synapses across diverse brain regions, there are differences in the mechanisms that often reveal the specific functional requirements of the brain area under study. Here we will review AMPAR regulation underlying synaptic plasticity in hippocampus and neocortex. The main focus of this review will be placed on postsynaptic forms of synaptic plasticity that impinge on the regulation of AMPARs using hippocampal CA1 and primary sensory cortices as examples. And through the comparison, we will highlight the key similarities and functional differences between the two synapses.     

Novel Bursting Patterns Emerging from Model Inhibitory Networks with Synaptic Depression

Studies show that short-term synaptic plasticity plays important roles in neural coding and the normal operation of the synapse. Basket cells in the hippocampus demonstrate this plasticity in the form of synaptic depression, and recent in vivo work indicates that basket cell activities contribute significantly to hippocampal output associated with different behavioural states. Thus it is essential to understand the generation and synchronization of patterns produced by basket cell networks with depression. We study two-cell model inhibitory networks with depression and obtain alternating bursting patterns and synchronous activity occurring between bursts. We describe mechanisms for how these patterns emerge by performing several simulations in the plane of different depression time constants, tauD. Such patterns might contribute significantly to various population activities observed in the hippocampus.     

Functional structure of the intermediate and ventral hippocampo–prefrontal pathway in the prefrontal convergent system

The hippocampo–prefrontal pathway is a unique projection that connects distant ends of the cerebral cortex. The direct hippocampo–prefrontal projection arises from the ventral to intermediate third of the hippocampus, but not from the dorsal third. It forms a funnel-shaped structure that collects information from the large hippocampal area and projects it to the prefrontal cortex. The anatomical regional differentiation of the projection has not been described. The hippocampal region is differentiated into structural and behavioural roles. For example, it has been shown that the ventral, but not the dorsal, hippocampus reciprocally connects with the amygdala and influences emotional behaviours. These data imply that hippocampal variation along the dorso–ventral axis is contained within the hippocampo–prefrontal pathway. Here, we present electrophysiological studies that demonstrate regional differences in short- but not long-term plasticity in the intermediate/posterior-dorsal and ventral routes of the hippocampo–prefrontal pathway. Furthermore, behavioural studies revealed that each route appears to play a different role in working memory. These results suggest that hippocampal regional information is processed through different routes, with the integration of individual regulatory functions in the prefrontal convergent system.     

Detrimental effects of chronic hypothalamic—pituitary—adrenal axis activation

Increasing evidence suggests that the detrimental effects of glucocorticoid (GC) hypersecretion occur by activation of the hypothalamic-pituitary-adrenal (HPA) axis in several human pathologies, including obesity, Alzheimer's disease, AIDS dementia, and depression. The different patterns of response by the HPA axis during chronic activation are an important consideration in selecting an animal model to assess HPA axis function in a particular disorder. This article will discuss how chronic HPA axis activation and GC hypersecretion affect hippocampal function and contribute to the development of obesity. In the brain, the hippocampus has the highest concentration of GC receptors. Chronic stress or corticosterone treatment induces neuropathological alterations, such as dendritic atrophy in hippocampal neurons, which are paralleled by cognitive deficits. Excitatory amino acid (EAA) neurotransmission has been implicated in chronic HPA axis activation. EAAs play a major role in neuroendocrine regulation. Hippocampal dendritic atrophy may involve alterations in EAA transporter function, and decreased EAA transporter function may also contribute to chronic HPA axis activation. Understanding the molecular mechanisms of HPA axis activation will likely advance the development of therapeutic interventions for conditions in which GC levels are chronically elevated.     

Contribution of cerebellar sensorimotor adaptation to hippocampal spatial memory

Complementing its primary role in motor control, cerebellar learning has also a bottom-up influence on cognitive functions, where high-level representations build up from elementary sensorimotor memories. In this paper we examine the cerebellar contribution to both procedural and declarative components of spatial cognition. To do so, we model a functional interplay between the cerebellum and the hippocampal formation during goal-oriented navigation. We reinterpret and complete existing genetic behavioural observations by means of quantitative accounts that cross-link synaptic plasticity mechanisms, single cell and population coding properties, and behavioural responses. In contrast to earlier hypotheses positing only a purely procedural impact of cerebellar adaptation deficits, our results suggest a cerebellar involvement in high-level aspects of behaviour. In particular, we propose that cerebellar learning mechanisms may influence hippocampal place fields, by contributing to the path integration process. Our simulations predict differences in place-cell discharge properties between normal mice and L7-PKCI mutant mice lacking long-term depression at cerebellar parallel fibre-Purkinje cell synapses. On the behavioural level, these results suggest that, by influencing the accuracy of hippocampal spatial codes, cerebellar deficits may impact the exploration-exploitation balance during spatial navigation.     

Antinociceptive activity of clonidine in the mouse, rat and dog

The antinociceptive activities of clonidine have been determined against several qualitatively different noxious stimuli in the mouse, rat and dog. In these tests clonidine given subcutaneously was 6 to 7 times more potent than morphine. Both clonidine and morphine were more potent against responses to heat induced nociceptive stimuli than against responses to heat induced nociception or that induced by electrical tail stimulation. However, unlike morphine the effects of clonidine in these latter tests were only seen at doses that also caused sedation and so these animals were less able to respond to the nociceptive stimuli. In contrast in pressure, chemical and tooth pulp stimulation tests clonidine produced increases in nociceptive thresholds at doses which caused no overt signs of behavioural depression. Comparisons of the relative potencies of clonidine and the less lipophilic analogue 4-hydroxyclonidine given subcutaneously and intracerebroventricularly indicate that clonidine induced antinociception is predominantly centrally mediated. However, a peripheral component may also be present in the inhibition of acetylcholine-induced abdominal constriction in the mouse.     

Depression and facilitation of synaptic responses in cat dorsal horn by substance P administered into substantia gelatinosa

The effects of substance P and an enkephalin analogue administered by electrophoresis into the substantia gelatinosa have been examined on the synaptic responses of dorsal horn neurons evoked by peripheral stimulation. Extracellular neuronal firing was studied in cats under pentobarbitone anesthesia. The enkephalin produced naloxone-reversible depression of responses to noxious heat stimulation without affecting responses to non-noxious stimuli. Substance P caused a selective enhancement or depression of noxious responses. It was tentatively concluded that substance P may modify the release of a sensory transmitter and produce direct post synaptic changes in membrane excitability.     

Long-term depression in the hippocampus in vivo is associated with protein phosphatase-dependent alterations in extracellular signal-regulated kinase

There is growing evidence that activation of either protein kinases or protein phosphatases determines the type of plasticity observed after different patterns of hippocampal stimulation. Because activation of the extracellular signal-regulated kinase (ERK) has been shown to be necessary for long-term potentiation, we investigated the regulation of ERK in long-term depression (LTD) in the adult hippocampus in vivo. We found that ERK immunoreactivity was decreased following the induction of LTD and that this decrease required NMDA receptor activation. The LTD-associated decrease in ERK immunoreactivity could be simulated in vitro via incubation of either purified ERK2 or hippocampal homogenates with either protein phosphatase 1 or protein phosphatase 2A. The protein phosphatase-dependent decrease in ERK immunoreactivity was inhibited by microcystin. Intrahippocampal administration of the protein phosphatase inhibitor okadaic acid blocked the LTD-associated decrease in ERK2, but not ERK1, immunoreactivity. Collectively, these data demonstrate that protein phosphatases can decrease ERK immunoreactivity and that such a decrease occurs with ERK2 during LTD. These observations provide the first demonstration of a biochemical alteration of ERK in LTD.     

Dopaminergic transmission in STOP null mice

Neuroleptics are thought to exert their anti-psychotic effects by counteracting a hyper-dopaminergic transmission. Here, we have examined the dopaminergic status of STOP (stable tubule only polypeptide) null mice, which lack a microtubule-stabilizing protein and which display neuroleptic-sensitive behavioural disorders. Dopamine transmission was investigated using both behavioural analysis and measurements of dopamine efflux in different conditions. Compared to wild-type mice in basal conditions or following mild stress, STOP null mice showed a hyper-locomotor activity, which was erased by neuroleptic treatment, and an increased locomotor reactivity to amphetamine. Such a behavioural profile is indicative of an increased dopaminergic transmission. In STOP null mice, the basal dopamine concentrations, measured by quantitative microdialysis, were normal in both the nucleus accumbens and the striatum. When measured by electrochemical techniques, the dopamine efflux evoked by electrical stimulations mimicking physiological stimuli was dramatically increased in the nucleus accumbens of STOP null mice, apparently due to an increased dopamine release, whereas dopaminergic uptake and auto-inhibition mechanisms were normal. In contrast, dopamine effluxes were slightly diminished in the striatum. Together with previous results, the present study indicates the association in STOP null mice of hippocampal hypo-glutamatergy and of limbic hyper-dopaminergy. Such neurotransmission defects are thought to be central to mental diseases such as schizophrenia.     

Regulation of Kainate Receptor Subunit mRNA by Stress and Corticosteroids in the Rat Hippocampus

Kainate receptors are a class of ionotropic glutamate receptors that have a role in the modulation of glutamate release and synaptic plasticity in the hippocampal formation. Previous studies have implicated corticosteroids in the regulation of these receptors and recent clinical work has shown that polymorphisms in kainate receptor subunit genes are associated with susceptibility to major depression and response to anti-depressant treatment. In the present study we sought to examine the effects of chronic stress and corticosteroid treatments upon the expression of the mRNA of kainate receptor subunits GluR5-7 and KA1-2. Our results show that, after 7 days, adrenalectomy results in increased expression of hippocampal KA1, GluR6 and GluR7 mRNAs, an effect which is reversed by treatment with corticosterone in the case of KA1 and GluR7 and by aldosterone treatment in the case of GluR6. 21 days of chronic restraint stress (CRS) elevated the expression of the KA1 subunit, but had no effect on the expression of the other subunits. Similarly, 21 days of treatment with a moderate dose of corticosterone also increased KA1 mRNA in the dentate gyrus, whereas a high corticosterone dose has no effect. Our results suggest an interaction between hippocampal kainate receptor composition and the hypothalamic-pituitary-adrenal (HPA) axis and show a selective chronic stress induced modulation of the KA1 subunit in the dentate gyrus and CA3 that has implications for stress-induced adaptive structural plasticity.