Age-associated alteration of innate defensive response to a looming stimulus and brain functional connectivity pattern in mice.

Innate defensive behaviors are essential for species survival. While these behaviors start to develop early in an individual's life, there is still much to be understood about how they evolve with advancing age. Considering that aging is often accompanied by various cognitive and physical declines, we tested the hypothesis that innate fear behaviors and underlying cerebral mechanisms are modified by aging. In our study we investigated this hypothesis by examining how aged mice respond to a looming visual threat compared to their younger counterparts. Our findings indicate that aged mice exhibit a different fear response than young mice when facing this imminent threat. Specifically, unlike young mice, aged mice tend to predominantly display freezing behavior without seeking shelter. Interestingly, this altered behavioral response in aged mice is linked to a distinct pattern of functional brain connectivity compared to young mice. Notably, our data highlights a lack of a consistent brain activation following the fear response in aged mice, suggesting that innate defensive behaviors undergo changes with aging.

Ventral tegmental area dopamine projections to the hippocampus trigger long-term potentiation and contextual learning.

In most models of neuronal plasticity and memory, dopamine is thought to promote the long-term maintenance of Long-Term Potentiation (LTP) underlying memory processes, but not the initiation of plasticity or new information storage. Here, we used optogenetic manipulation of midbrain dopamine neurons in male DAT::Cre mice, and discovered that stimulating the Schaffer collaterals - the glutamatergic axons connecting CA3 and CA1 regions - of the dorsal hippocampus concomitantly with midbrain dopamine terminals within a 200 millisecond time-window triggers LTP at glutamatergic synapses. Moreover, we showed that the stimulation of this dopaminergic pathway facilitates contextual learning in awake behaving mice, while its inhibition hinders it. Thus, activation of midbrain dopamine can operate as a teaching signal that triggers NeoHebbian LTP and promotes supervised learning.

No major effect of dopamine receptor 1/5 antagonist SCH-23390 on epileptic activity in the Tg2576 mouse model of amyloidosis.

The excitation-inhibition imbalance manifesting as epileptic activities in Alzheimer's disease is gaining more and more attention, and several potentially involved cellular and molecular pathways are currently under investigation. Based on in vitro studies, dopamine D1-type receptors in the anterior cingulate cortex and the hippocampus have been proposed to participate in this peculiar co-morbidity in mouse models of amyloidosis. Here, we tested the implication of dopaminergic transmission in vivo in the Tg2576 mouse model of Alzheimer's disease by monitoring epileptic activities via intracranial EEG before and after treatment with dopamine antagonists. Our results show that neither the D1-like dopamine receptor antagonist SCH23390 nor the D2-like dopamine receptor antagonist haloperidol reduces the frequency of epileptic activities. While requiring further investigation, our results indicate that on a systemic level, dopamine receptors are not significantly contributing to epilepsy observed in vivo in this mouse model of Alzheimer's disease.

Enriched environmental exposure reduces the onset of action of the serotonin norepinephrin reuptake inhibitor venlafaxine through its effect on parvalbumin interneurons plasticity in mice.

Mood disorders are associated with hypothalamic-pituitary-adrenal axis overactivity resulting from a decreased inhibitory feedback exerted by the hippocampus on this brain structure. Growing evidence suggests that antidepressants would regulate hippocampal excitatory/inhibitory balance to restore an effective inhibition on this stress axis. While these pharmacological compounds produce beneficial clinical effects, they also have limitations including their long delay of action. Interestingly, non-pharmacological strategies such as environmental enrichment improve therapeutic outcome in depressed patients as in animal models of depression. However, whether exposure to enriched environment also reduces the delay of action of antidepressants remains unknown. We investigated this issue using the corticosterone-induced mouse model of depression, submitted to antidepressant treatment by venlafaxine, alone or in combination with enriched housing. We found that the anxio-depressive phenotype of male mice was improved after only two weeks of venlafaxine treatment when combined with enriched housing, which is six weeks earlier than mice treated with venlafaxine but housed in standard conditions. Furthermore, venlafaxine combined with exposure to enriched environment is associated with a reduction in the number of parvalbumin-positive neurons surrounded by perineuronal nets (PNN) in the mouse hippocampus. We then showed that the presence of PNN in depressed mice prevented their behavioral recovery, while pharmacological degradation of hippocampal PNN accelerated the antidepressant action of venlafaxine. Altogether, our data support the idea that non-pharmacological strategies can shorten the onset of action of antidepressants and further identifies PV interneurons as relevant actors of this effect.

Neuronal hyperexcitability in the Tg2576 mouse model of Alzheimer's disease - the influence of sleep and noradrenergic transmission.

The link between Alzheimer's disease (AD) and network hypersynchrony - manifesting as epileptic activities - received considerable attention in the past decade. However, several questions remain unanswered as to its mechanistic underpinnings. Therefore, our objectives were (1) to better characterise epileptic events in the Tg2576 mouse model throughout the sleep-wake cycle and disease progression via electrophysiological recordings and (2) to explore the involvement of noradrenergic transmission in this pathological hypersynchrony. Over and above confirming the previously described early presence and predominance of epileptic events during rapid-eye-movement (REM) sleep, we also show that these events do not worsen with age and are highly phase-locked to the section of the theta cycle during REM sleep where hippocampal pyramidal cells reach their highest firing probability. Finally, we reveal an antiepileptic mechanism of noradrenergic transmission via α1-adrenoreceptors that could explain the intriguing distribution of epileptic events over the sleep-wake cycle in this model, with potential therapeutic implications in the treatment of the epileptic events occurring in many AD patients.

Astroglial Connexins Inactivation Increases Relapse of Depressive-like Phenotype after Antidepressant Withdrawal.

Studies suggest that astrocytic connexins (Cx) have an important role in the regulation of high brain functions through their ability to establish fine-tuned communication with neurons within the tripartite synapse. In light of these properties, growing evidence suggests a role of Cx in psychiatric disorders such as major depression but also in the therapeutic activity of antidepressant drugs. However, the real impact of Cx on treatment response and the underlying neurobiological mechanisms remain yet to be clarified. On this ground, the present study was designed to evaluate the functional activity of Cx in a mouse model of depression based on chronic corticosterone exposure and to determine to which extent their pharmacological inactivation influences the antidepressant-like activity of venlafaxine (VENLA). On the one hand, our results indicate that depressed mice have impaired Cx-based gap-junction and hemichannel activities. On the other hand, while VENLA exerts robust antidepressant-like activity in depressed mice; this effect is abolished by the pharmacological inhibition of Cx with carbenoxolone (CBX). Interestingly, the combination of VENLA and CBX is also associated with a higher rate of relapse after treatment withdrawal. To our knowledge, this study is one of the first to develop a model of relapse, and our results reveal that Cx-mediated dynamic neuroglial interactions play a critical role in the efficacy of monoaminergic antidepressant drugs, thus providing new targets for the treatment of depression.

Altered inhibitory function in hippocampal CA2 contributes in social memory deficits in Alzheimer's mouse model.

Parvalbumin (PV)-expressing interneurons which are often associated with the specific extracellular matrix perineuronal net (PNN) play a critical role in the alteration of brain activity and memory performance in Alzheimer's disease (AD). The integrity of these neurons is crucial for normal functioning of the hippocampal subfield CA2, and hence, social memory formation. Here, we find that social memory deficits of mouse models of AD are associated with decreased presence of PNN around PV cells and long-term synaptic plasticity in area CA2. Furthermore, single local injection of the growth factor neuregulin-1 (NRG1) is sufficient to restore both PV/PNN levels and social memory performance of these mice. Thus, the PV/PNN disruption in area CA2 could play a causal role in social memory deficits of AD mice, and activating PV cell pro-maturation pathways may be sufficient to restore social memory.

Efficacy of THN201, a Combination of Donepezil and Mefloquine, to Reverse Neurocognitive Deficits in Alzheimer's Disease.

Donepezil (DPZ) is an acetylcholinesterase inhibitor used in Alzheimer's disease to restore cognitive functions but is endowed with limited efficacy. Recent studies pointed out the implication of astroglial networks in cognitive processes, notably via astrocyte connexins (Cxs), proteins involved in gap junction intercellular communications. Hence, we investigated the impact on cognition of pharmacological or genetic modulations of those astrocyte Cxs during DPZ challenge in two rodent models of Alzheimer's disease-like memory deficits. We demonstrated that the Cx modulator mefloquine (MEF) significantly enhanced the procognitive effect of DPZ in both models. In parallel, we determined that MEF potentiated DPZ-induced release of acetylcholine in hippocampus. Finally, local genetic silencing of astrocyte Cxs in the hippocampus was also found to enhance the procognitive effect of DPZ, pointing out the importance of Cx-dependent astrocyte networks in memory processes.

Transcriptional corepressor SIN3A regulates hippocampal synaptic plasticity via Homer1/mGluR5 signaling.

Long-term memory depends on the control of activity-dependent neuronal gene expression, which is regulated by epigenetic modifications. The epigenetic modification of histones is orchestrated by the opposing activities of 2 classes of regulatory complexes: permissive coactivators and silencing corepressors. Much work has focused on coactivator complexes, but little is known about the corepressor complexes that suppress the expression of plasticity-related genes. Here, we define a critical role for the corepressor SIN3A in memory and synaptic plasticity, showing that postnatal neuronal deletion of Sin3a enhances hippocampal long-term potentiation and long-term contextual fear memory. SIN3A regulates the expression of genes encoding proteins in the postsynaptic density. Loss of SIN3A increases expression of the synaptic scaffold Homer1, alters the metabotropic glutamate receptor 1α (mGluR1α) and mGluR5 dependence of long-term potentiation, and increases activation of ERK in the hippocampus after learning. Our studies define a critical role for corepressors in modulating neural plasticity and memory consolidation and reveal that Homer1/mGluR signaling pathways may be central molecular mechanisms for memory enhancement.

Genetic and pharmacological inactivation of astroglial connexin 43 differentially influences the acute response of antidepressant and anxiolytic drugs.

AIM: Astroglial connexins (Cxs) 30 and 43 are engaged in gap junction and hemichannel activities. Evidence suggests that these functional entities contribute to regulating neurotransmission, thereby influencing brain functions. In particular, preclinical and clinical findings highlight a role of Cx43 in animal models of depression. However, the role of these proteins in response to currently available psychotropic drugs is still unknown. METHODS: To investigate this, we evaluated the behavioural effects of the genetic and pharmacological inactivation of Cx43 on the antidepressant- and anxiolytic-like activities of the selective serotonin reuptake inhibitor fluoxetine and the benzodiazepine diazepam, respectively. RESULTS: A single administration of fluoxetine (18 mg/kg; i.p.) produced a higher increase in hippocampal extracellular serotonin levels, and a greater antidepressant-like effect in the tail suspension test in Cx43 knock-down (KD) mice bred on a C57BL/6 background compared to their wild-type littermates. Similarly, in outbred Swiss wild-type mice, the intra-hippocampal injection of a shRNA-Cx43 or the acute systemic injection of the Cxs inhibitor carbenoxolone (CBX: 10 mg/kg; i.p.) potentiated the antidepressant-like effects of fluoxetine. Evaluating the effects of such strategies on diazepam (0.5 mg/kg; i.p.), the results indicate that Cx43 KD mice or wild-types injected with a shRNA-Cx43 in the amygdala, but not in the hippocampus, attenuated the anxiolytic-like effects of this benzodiazepine in the elevated plus maze. The chronic systemic administration of CBX mimicked the latter observations. CONCLUSION: Collectively, these data pave the way to the development of potentiating strategies in the field of psychiatry based on the modulation of astroglial Cx43.

Early disruption of parvalbumin expression and perineuronal nets in the hippocampus of the Tg2576 mouse model of Alzheimer's disease can be rescued by enriched environment.

Recent findings show that parvalbumin (PV) interneuron function is impaired in Alzheimer's disease (AD), and that this impairment in PV function can be linked to network dysfunction and memory deficits. PV cells are often associated with a specific extracellular matrix, the perineuronal net (PNN). PNNs are believed to protect PV cell integrity, and whether the amyloidopathy affects PNNs remains unclear. Here, we evaluated the number of PV cells with and without PNNs in the hippocampus of the Tg2576 mouse model of AD at different stages of the disease. We show a deficit of PV+ and/or PV+/PNN+ cells in the areas CA1, CA2, and CA3 in Tg2576 as young as 3 months of age. Importantly, transient exposure to an enriched environment, which has proven long-lasting beneficial effects on memory in AD subjects, rescues the PV/PNN cell number deficits. We conclude that cognitive improvements induced by enriched environment in AD mouse models could be supported by a remodeling of hippocampal PV cell network and their PNNs.

Processing of Egomotion-Consistent Optic Flow in the Rhesus Macaque Cortex.

The cortical network that processes visual cues to self-motion was characterized with functional magnetic resonance imaging in 3 awake behaving macaques. The experimental protocol was similar to previous human studies in which the responses to a single large optic flow patch were contrasted with responses to an array of 9 similar flow patches. This distinguishes cortical regions where neurons respond to flow in their receptive fields regardless of surrounding motion from those that are sensitive to whether the overall image arises from self-motion. In all 3 animals, significant selectivity for egomotion-consistent flow was found in several areas previously associated with optic flow processing, and notably dorsal middle superior temporal area, ventral intra-parietal area, and VPS. It was also seen in areas 7a (Opt), STPm, FEFsem, FEFsac and in a region of the cingulate sulcus that may be homologous with human area CSv. Selectivity for egomotion-compatible flow was never total but was particularly strong in VPS and putative macaque CSv. Direct comparison of results with the equivalent human studies reveals several commonalities but also some differences.