Hippocampal Plasticity Research Articles

Epinephrine injected into the basolateral amygdala affects anxiety-like behavior and memory performance in stressed rats

The amygdala is known to mediate in moderating the impacts of emotional arousal and stress on memory. According to a growing body of research, the basolateral amygdala (BLA) is an important locus for integrating neuromodulator influences coordinating the retrieval of different types of memory and anxiety. This study aimed to investigate how the epinephrine in the BLA affects hippocampal fear memory, anxiety, and plasticity in control and stressed rats. For four days, male Wistar rats were exposed to electrical foot-shock stress. Animals received bilateral micro-injections of either vehicle or epinephrine (1 µg/side) into the BLA over four days (5 min before foot-shock stress). Behavioral characteristics (fear memory and anxiety-like behavior), histological features and electrophysiological parameters were investigated. Epinephrine injection into BLA resulted in a considerable impairment of fear memory in stressed rats. On the other hand, epinephrine effectively affected fear memory in control rats. Under stress conditions, epinephrine in the BLA is thought to increase anxiety-like behaviors. Treatment with epinephrine significantly increases the slope of fEPSP in the CA1 region of the hippocampus in the control and stress rats. In different groups, foot-shock stress had no effect on the apical and basal dendritic length in the CA1 region of the hippocampus. These results indicate that activating adrenergic receptors diminish fear memory and anxiety-like behaviors in the foot-shock stress, which this impact is independent of CA1 long-term potentiation induction.

A role for MCH neuron firing in modulating hippocampal plasticity threshold

It has been revealed that hypothalamic neurons containing the peptide, melanin-concentrating hormone (MCH) can influence learning [1] and memory formation [2], but the cellular mechanisms by which they perform this function are not well understood. Here, we examine the role of MCH neural input to the hippocampus, and show in vitro that optogenetically increasing MCH axon activity facilitates hippocampal plasticity by lowering the threshold for synaptic potentiation. These results align with increasing evidence that MCH neurons play a regulatory role in learning, and reveal that this could be achieved by modulating plasticity thresholds in the hippocampus.

CAMP-dependent protein kinase signaling is required for (2R,6R)-hydroxynorketamine to potentiate hippocampal glutamatergic transmission.

(2R,6R)-Hydroxynorketamine (HNK) is a ketamine metabolite that shows rapid antidepressant-like effects in preclinical studies and lacks the adverse N-methyl-d-aspartate receptor (NMDAR) inhibition-related properties of ketamine. Investigating how (2R,6R)-HNK exerts its antidepressant actions may be informative in the design of novel pharmacotherapies with improved safety and efficacy. We sought to identify the molecular substrates through which (2R,6R)-HNK induces functional changes at excitatory synapses, a prevailing hypothesis for how rapid antidepressant effects are initiated. We recorded excitatory postsynaptic potentials in hippocampal slices from male Wistar Kyoto rats, which have impaired hippocampal plasticity and are resistant to traditional antidepressants. (2R,6R)-HNK (10 µM) led to a rapid potentiation of electrically evoked excitatory postsynaptic potentials at Schaffer collateral CA1 stratum radiatum synapses. This potentiation was associated with a decrease in paired pulse facilitation, suggesting an increase in the probability of glutamate release. The (2R,6R)-HNK-induced potentiation was blocked by inhibiting either cyclic adenosine monophosphate (cAMP) or its downstream target, cAMP-dependent protein kinase (PKA). As cAMP is a potent regulator of brain-derived neurotrophic factor (BDNF) release, we assessed whether (2R,6R)-HNK exerts this acute potentiation through a rapid increase in cAMP-dependent BDNF-TrkB signaling. We found that the cAMP-PKA-dependent potentiation was not dependent on TrkB activation by BDNF, which functionally delimits the acute synaptic effects of (2R,6R)-HNK from its sustained BDNF-dependent actions in vivo. These results suggest that, by potentiating glutamate release via cAMP-PKA signaling, (2R,6R)-HNK initiates acute adaptations in fast excitatory synaptic transmission that promote structural plasticity leading to maintained antidepressant action.NEW & NOTEWORTHY Ketamine is a rapid-acting antidepressant and its preclinical effects are mimicked by its (2R,6R)-(HNK) metabolite. We found that (2R,6R)-HNK initiates acute adaptations in fast excitatory synaptic transmission by potentiating glutamate release via cAMP-PKA signaling at hippocampal Schaffer collateral synapses. This cAMP-PKA-dependent potentiation was not dependent on TrkB activation by BDNF, which functionally delimits the rapid synaptic effects of (2R,6R)-HNK from its sustained BDNF-dependent actions that are thought to maintain antidepressant action in vivo.

Imaging the brain to assess brain insulin action

AbstractBackgroundEver since the brain was identified as an insulin‐sensitive organ, it was quickly appreciated that insulin action in the brain affects cognitive and metabolic processes [1]. Epidemiological evidence suggests a strong link between reduced peripheral insulin sensitivity and age‐related neurodegenerative processes, including Alzheimer’s disease (AD) [2].MethodCharacterization of brain insulin resistance in humans is challenging and relies on different neuroimaging methods in combination with insulin stimulation techniques. In my talk, I will focus on the administration of intranasal insulin, which has been established over the last decades to disentangle peripheral from brain insulin effects [1]. In combination with functional neuroimaging, I will show recent data on the quantification of brain insulin sensitivity non‐invasively in humans of different age and weight groups [3].ResultWe could show that intranasal insulin can affect region‐specific activity and functional connectivity of the human brain. These diverse central insulin responses largely depend on its action in the hypothalamus, amygdala, hippocampus, striatum and parts of the insula and prefrontal cortex and influences a variety of metabolic and cognitive processes [3]. Specifically, I will show that disrupted brain insulin action can result in increased accumulation of visceral fat and altered reward learning in persons at high risk to develop T2D [4], but also in healthy individuals after overconsumption of high caloric foods (unpublished). Moreover, I will show that the effect of intranasal insulin in the hippocampus decreases with age in women but not men and that brain insulin responsivity is affected by the menstrual cycle (unpublished). Moreover, just recently, we could link enhanced brain insulin action in the mesocorticolimbic circuitry with improved cognitive and metabolic functions [5].ConclusionAs brain insulin acts on striatal dopamine function and hippocampal plasticity, enhancing brain insulin action could lead to new treatment options in diabetes and aging‐associated diseases.

The Edible Seaweed Gelidium amansii Promotes Structural Plasticity of Hippocampal Neurons and Improves Scopolamine-Induced Learning and Memory Impairment in Mice.

Gelidium amansii has been gaining profound interest in East Asian countries due to its enormous commercial value for agar production and its extensive pharmacological properties. Previous studies have shown that the ethanol extract of Gelidium amansii (GAE) has promising neurotrophic effects in in vitro conditions. The present study aimed at investigating the protective effects of GAE against scopolamine-induced cognitive deficits and its modulatory effects on hippocampal plasticity in mice. For memory-related behavioral studies, the passive avoidance test and radial arm maze paradigm were conducted. The brain slices of the hippocampus CA1 neurons of experimental mice were then prepared to perform Golgi staining for analyzing spine density and its characteristic shape, and immunohistochemistry for assessing the expression of different pre- and postsynaptic proteins. Following oral administration of GAE (0.5 mg/g body weight), mice with memory deficits exhibited a significant increase in the latency time on the passive avoidance test and a decrease in the number of working and reference memory errors and latency time on the radial arm maze test. Microscopic observations of Golgi-impregnated tissue sections and immunohistochemistry of hippocampal slices showed that neurons from GAE-treated mice displayed higher spine density and spine dynamics, increased synaptic contact, and the recruitment of memory-associated proteins such as N-methyl-D-aspartate receptors (NR2A and NR2B) and postsynaptic density-95 (PSD-95) when compared with the control group. With these memory-protective functions and a modulatory role in underlying memory-related events, GAE could be a potential functional food and a promising source of pharmacological agents for the prevention and treatment of memory-related brain disorders.

Selective inhibition of soluble TNF using XPro1595 improves hippocampal pathology to promote improved neurological recovery following traumatic brain injury in mice.

To determine the efficacy of XPro1595 to improve pathophysiological and functional outcomes in a mouse model of traumatic brain injury (TBI). Symptoms associated with TBI can be debilitating, and treatment without off-target side effects remains a challenge. This study aimed to investigate the efficacy of selectively inhibiting the soluble form of TNF (solTNF) using the biologic XPro1595 in a mouse model of TBI. Use XPro1595 to determine whether injury-induced solTNF promotes hippocampal inflammation and dendritic plasticity, and associated functional impairments. Mild-to-moderate traumatic brain injury (CCI model) was induced in adult male C57Bl/6J WT and Thy1-YFPH mice, with XPro1595 (10 mg/kg, S.C.) or vehicle being administered in a clinically relevant window (60 minutes post-injury). The animals were assessed for differences in neurological function, and hippocampal tissue was analyzed for inflammation and glial reactivity, as well as neuronal degeneration and plasticity. We report that unilateral CCI over the right parietal cortex in mice promoted deficits in learning and memory, depressive-like behavior, and neuropathic pain. Using immunohistochemical and Western blotting techniques, we observed the cortical injury promoted a set of expected pathophysiology's within the hippocampus consistent with the observed neurological outcomes, including glial reactivity, enhanced neuronal dendritic degeneration (dendritic beading), and reduced synaptic plasticity (spine density and PSD-95 expression) within the DG and CA1 region of the hippocampus, that were prevented in mice treated with XPro1595. Overall, we observed that selectively inhibiting solTNF using XPro1595 improved the pathophysiological and neurological sequelae of brain-injured mice, which provides support for its use in patients with TBI.

Synaptic BMAL1 phosphorylation controls circadian hippocampal plasticity.

The time of day strongly influences adaptive behaviors like long-term memory, but the correlating synaptic and molecular mechanisms remain unclear. The circadian clock comprises a canonical transcription-translation feedback loop (TTFL) strictly dependent on the BMAL1 transcription factor. We report that BMAL1 rhythmically localizes to hippocampal synapses in a manner dependent on its phosphorylation at Ser42 [pBMAL1(S42)]. pBMAL1(S42) regulates the autophosphorylation of synaptic CaMKIIα and circadian rhythms of CaMKIIα-dependent molecular interactions and LTP but not global rest/activity behavior. Therefore, our results suggest a model in which repurposing of the clock protein BMAL1 to synapses locally gates the circadian timing of plasticity.

Effect of Suanzaoren Decoction on expression of ionotropic glutamate receptors and synaptic plasticity in hippocampus of anxiety rats

This study investigated the effect of Suanzaoren Decoction on the expression of N-methyl-D-aspartate receptors(NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors(AMPAR) in the hippocampus and synaptic plasticity in rats with conditioned fear-induced anxiety. The effect of Suanzaoren Decoction on rat behaviors were evaluated through open field experiment, elevated plus maze experiment, and light/dark box experiment. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of glutamate(Glu) and γ-aminobutyric acid(GABA) in the rat hippocampus. Real-time fluorescence quantitative PCR(qRT-PCR) and Western blot were employed to assess the gene and protein expression of ionotropic glutamate receptors in the hippocampal region. Transmission electron microscopy was utilized to observe the changes in the ultrastructure of synaptic neurons in the hippocampal region. Long-term potentiation(LTP) detection technique was employed to record the changes in population spike(PS) amplitude in the hippocampal region of mice in each group. The behavioral results showed that compared with the model group, the Suanzaoren Decoction group effectively increased the number of entries into open arms, time spent in open arms, percentage of time spent in open arms out of total movement time, number of entries into open arms out of total entries into both arms(P<0.01), and significantly increased the time spent in the light box and the number of shuttle crossings(P<0.01). There was an increasing trend in the number of grid crossings, entries into the center grid, and time spent in the center grid, indicating a significant anxiolytic effect. ELISA results showed that compared with the model group, the Suanzaoren Decoction group exhibited significantly reduced levels of Glu, Glu/GABA ratio(P<0.01), and significantly increased levels of GABA(P<0.01) in the rat hippocampus. Furthermore, Suanzaoren Decoction significantly decreased the gene and protein expression of NMDAR(GluN2B and GluN2A) and AMPAR(GluA1 and GluA2) compared with the model group. Transmission electron microscopy results demonstrated improvements in synapses, neuronal cells, and organelles in the hippocampal region of the Suanzaoren Decoction group compared with the model group. LTP detection results showed a significant increase in the PS amplitude changes in the hippocampal region of Suanzaoren Decoction group from 5 to 35 min compared with the model group(P<0.05, P<0.01). In conclusion, Suanzaoren Decoction exhibits significant anxiolytic effects, which may be attributed to the reduction in NMDAR and AMPAR expression levels and the improvement of synaptic plasticity.

After-effects of repetitive transcranial magnetic stimulation with parameter dependence on long-term potentiation-like plasticity and object recognition memory in rats.

To investigate the after-effects of 25-Hz repetitive transcranial magnetic stimulation (rTMS) at 60, 100, and 120% resting motor threshold (rMT) on long-term potentiation (LTP) in the rat hippocampus, to clarify the intensity dependence of rTMS, and to determine whether it simultaneously affects learning and memory ability. Five rats were randomly selected from 70 male Wistar rats, and evoked rMT potentials were recorded in response to magnetic stimulation. The remaining 65 rats were randomly assigned to five groups (n = 13), including sham rTMS, 1 Hz 100% rMT, and 25 Hz rTMS groups with 3 subgroups of 60% rMT, 100% rMT, and 120% rMT. Five rats in each group were anesthetized and induced by a priming TMS-test design for population spike (PS) response of the perforant path-dentate gyrus in the hippocampus; the remaining eight rats in each group were evaluated for object recognition memory in the novel object recognition (NOR) task after the different rTMS protocols. Forty-five percent (approximately 1.03 T) of the magnetic stimulator output was confirmed as rMT in the biceps femoris muscle. The PS ratio was ranked as follows: 25 Hz 100% rMT (267.78 ± 25.71%) > sham rTMS (182 ± 9.4%) >1 Hz 100% rMT (102.69 ± 6.64%) > 25 Hz 120% rMT (98 ± 11.3%) > 25 Hz 60% rMT (36 ± 8.5%). Significant differences were observed between the groups, except for the difference between the 25 Hz 120% rMT and the 1 Hz 100% rMT groups (p = 0.446). LTP was successfully induced over the 60-min recording period only in the sham rTMS and 25 Hz 100% rMT groups. Moreover, these two groups spent more time exploring a novel object than a familiar object during the NOR task (p < 0.001), suggesting long-term recognition memory retention. In the between-group analysis of the discrimination index, the following ranking was observed: 25 Hz 100% rMT (0.812 ± 0.158) > sham rTMS (0.653 ± 0.111) > 25 Hz 120% rMT (0.583 ± 0.216) >1 Hz 100% rMT (0.581 ± 0.145) > 25 Hz 60% rMT (0.532 ± 0.220). The after-effect of 25-Hz rTMS was dependent on stimulus intensity and provided an inverted (V-shaped) bidirectional modulation on hippocampal plasticity that involved two forms of metaplasticity. Furthermore, the effects on the recognition memory ability were positively correlated with those on LTP induction in the hippocampus in vivo.

Transcriptome analysis of the effects of maternal fructose exposure during gestation and lactation on the cytoskeleton of offspring hippocampus

Excessive fructose consumption poses a public health concern. Maternal fructose overconsumption impairs offspring hippocampal function, indicating hippocampal sensitivity to fructose. The hippocampus is the vital for spatial learning and memory, and the cytoskeletal structure is crucial for hippocampal neuronal plasticity. The Rho GTPase is a key regulator of neuronal cytoskeleton formation, with RhoA protein governing neuronal growth and development. The RhoA/ROCK2 pathway affects myosin light chain phosphorylation, leading to cytoskeletal reorganization, actin cytoskeleton changes, and neurite retraction. However, the effects of maternal fructose exposure during gestation and lactation on the offspring's neural cytoskeleton remain unclear. We established maternal fructose exposure models during gestation and lactation, assessing fasting blood glucose levels in offspring confirm model effectiveness. Whole transcriptome sequencing examined offspring hippocampal developmental programming. Immunofluorescence and Western blot analyses assessed RhoA/ROCK2 pathway expression changes in the hippocampus, with PCR validating transcriptome sequencing results. Transcriptome sequencing identified 193 and 298 differentially expressed genes in the control, 13% fructose, and 40% fructose groups, respectively. GO and KEGG analyses revealed significant changes related to neural development, learning memory, and cytoskeleton in both fructose-exposed groups. GSEA indicated substantial cytoskeleton-related alterations in the offspring. Immunofluorescence demonstrated significant CRMP2 protein down-regulation in both fructose-exposed groups. Western blotting showed significantly higher expression of RhoA, ROCK2, p-ROCK2, and p-MLC2 in the fructose-exposed groups (P < 0.05). Maternal high-fructose exposure significantly impacts gene expression in offspring. These alterations may influence hippocampal neurodevelopment by up-regulating the RhoA/ROCK2 pathway, leading to cytoskeletal damage and axon growth inhibition.

Multiple routes to enhanced memory for emotionally relevant events.

Events associated with aversive or rewarding outcomes are prioritized in memory. This memory boost is commonly attributed to the elicited affective response, closely linked to noradrenergic and dopaminergic modulation of hippocampal plasticity. Herein we review and compare this 'affect' mechanism to an additional, recently discovered, 'prediction' mechanism whereby memories are strengthened by the extent to which outcomes deviate from expectations, that is, by prediction errors (PEs). The mnemonic impact of PEs is separate from the affective outcome itself and has a distinct neural signature. While both routes enhance memory, these mechanisms are linked to different - and sometimes opposing - predictions for memory integration. We discuss new findings that highlight mechanisms by which emotional events strengthen, integrate, and segment memory.

Music Therapy as a Low-Cost Treatment for Alzheimer’s Disease

Introduction Alzheimer's disease affects over 55 million people globally, projected to double by 2030 and triple by 2050. It ranks among the top 10 causes of death, necessitating urgent treatment and cures. Music therapy positively impacts brain development and plasticity, particularly in the medial temporal lobe. It shows promise as a therapeutic approach for enhancing neuroplasticity in the hippocampus, benefiting individuals with Alzheimer's disease. Materials and Methods This review explores music therapy as a cost-effective and side-effect-free avenue for patients to alleviate neurodegenerative symptoms based on the analysis of 21 other articles published by renowned authors. Discussion Alzheimer's disease causes hippocampal abnormalities and cognitive decline. Music, with musical mnemonics and enhanced working memory, shows promise for memory improvement. Music therapy induces neuroplasticity, potentially treating hippocampal neuron loss. Vocal training improves psychomotor speed and reduces dementia symptoms. Further exploration of music therapy may offer novel strategies for alleviating Alzheimer's symptoms and benefiting neurological disorders. Mechanisms underlying therapeutic benefits require further investigation. Music therapy holds inherent potential for Alzheimer's and related neurodegenerative diseases. Conclusion Empirical evidence shows musical training enhances hippocampal plasticity and gray matter volume, suggesting music therapy may treat hippocampal neuron loss in Alzheimer's disease, improving working memory. It holds promise for Alzheimer's and related neurodegenerative disorders by enhancing hippocampal function, but further research on underlying mechanisms is needed.

From Youthful Vigor to Aging Decline: Unravelling the Intrinsic and Extrinsic Determinants of Hippocampal Neural Stem Cell Aging.

Since Joseph Altman published his pioneering work demonstrating neurogenesis in the hippocampus of adult rats, the number of publications in this field increased exponentially. Today, we know that the adult hippocampus harbors a pool of adult neural stem cells (NSCs) that are the source of life-long neurogenesis and plasticity. The functions of these NSCs are regulated by extrinsic cues arising from neighboring cells and the systemic environment. However, this tight regulation is subject to imbalance with age, resulting in a decline in adult NSCs and neurogenesis, which contributes to the progressive deterioration of hippocampus-related cognitive functions. Despite extensive investigation, the mechanisms underlying this age-related decline in neurogenesis are only incompletely understood, but appear to include an increase in NSC quiescence, changes in differentiation patterns, and NSC exhaustion. In this review, we summarize recent work that has improved our knowledge of hippocampal NSC aging, focusing on NSC-intrinsic mechanisms as well as cellular and molecular changes in the niche and systemic environment that might be involved in the age-related decline in NSC functions. Additionally, we identify future directions that may advance our understanding of NSC aging and the concomitant loss of hippocampal neurogenesis and plasticity.

The Dysfunctional Mechanisms Throwing Tics: Structural and Functional Changes in Tourette Syndrome.

Tourette Syndrome (TS) is a high-incidence multifactorial neuropsychiatric disorder characterized by motor and vocal tics co-occurring with several diverse comorbidities, including obsessive-compulsive disorder and attention-deficit hyperactivity disorder. The origin of TS is multifactorial, with strong genetic, perinatal, and immunological influences. Although almost all neurotransmettitorial systems have been implicated in TS pathophysiology, a comprehensive neurophysiological model explaining the dynamics of expression and inhibition of tics is still lacking. The genesis and maintenance of motor and non-motor aspects of TS are thought to arise from functional and/or structural modifications of the basal ganglia and related circuitry. This complex wiring involves several cortical and subcortical structures whose concerted activity controls the selection of the most appropriate reflexive and habitual motor, cognitive and emotional actions. Importantly, striatal circuits exhibit bidirectional forms of synaptic plasticity that differ in many respects from hippocampal and neocortical plasticity, including sensitivity to metaplastic molecules such as dopamine. Here, we review the available evidence about structural and functional anomalies in neural circuits which have been found in TS patients. Finally, considering what is known in the field of striatal plasticity, we discuss the role of exuberant plasticity in TS, including the prospect of future pharmacological and neuromodulation avenues.

Local autocrine plasticity signaling in single dendritic spines by insulin-like growth factors.

The insulin superfamily of peptides is essential for homeostasis as well as neuronal plasticity, learning, and memory. Here, we show that insulin-like growth factors 1 and 2 (IGF1 and IGF2) are differentially expressed in hippocampal neurons and released in an activity-dependent manner. Using a new fluorescence resonance energy transfer sensor for IGF1 receptor (IGF1R) with two-photon fluorescence lifetime imaging, we find that the release of IGF1 triggers rapid local autocrine IGF1R activation on the same spine and more than several micrometers along the stimulated dendrite, regulating the plasticity of the activated spine in CA1 pyramidal neurons. In CA3 neurons, IGF2, instead of IGF1, is responsible for IGF1R autocrine activation and synaptic plasticity. Thus, our study demonstrates the cell type-specific roles of IGF1 and IGF2 in hippocampal plasticity and a plasticity mechanism mediated by the synthesis and autocrine signaling of IGF peptides in pyramidal neurons.

CBD enhances the cognitive score of adolescent rats prenatally exposed to THC and fine-tunes relevant effectors of hippocampal plasticity.

Introduction: An altered neurodevelopmental trajectory associated with prenatal exposure to ∆-9-tetrahydrocannabinol (THC) leads to aberrant cognitive processing through a perturbation in the effectors of hippocampal plasticity in the juvenile offspring. As adolescence presents a unique window of opportunity for "brain reprogramming", we aimed at assessing the role of the non-psychoactive phytocannabinoid cannabidiol (CBD) as a rescue strategy to temper prenatal THC-induced harm. Methods: To this aim, Wistar rats prenatally exposed to THC (2mg/kg s.c.) or vehicle (gestational days 5-20) were tested for specific indexes of spatial and configural memory in the reinforcement-motivated Can test and in the aversion-driven Barnes maze test during adolescence. Markers of hippocampal excitatory plasticity and endocannabinoid signaling-NMDAR subunits NR1 and 2A-, mGluR5-, and their respective scaffold proteins PSD95- and Homer 1-; CB1R- and the neuromodulatory protein HINT1 mRNA levels were evaluated. CBD (40mg/kg i.p.) was administered to the adolescent offspring before the cognitive tasks. Results: The present results show that prenatal THC impairs hippocampal memory functions and the underlying synaptic plasticity; CBD is able to mitigate cognitive impairment in both reinforcement- and aversion-related tasks and the neuroadaptation of hippocampal excitatory synapses and CB1R-related signaling. Discussion: While this research shows CBD potential in dampening prenatal THC-induced consequences, we point out the urgency to curb cannabis use during pregnancy in order to avoid detrimental bio-behavioral outcomes in the offspring.

Resveratrol Mediated Regulation of Hippocampal Neuroregenerative Plasticity via SIRT1 Pathway in Synergy with Wnt Signaling: Neurotherapeutic Implications to Mitigate Memory Loss in Alzheimer's Disease.

Alzheimer's disease (AD) is a major form of dementia. Abnormal amyloidogenic event-mediated degeneration of cholinergic neurons in the cognitive centers of the brain has been attributed to neuropathological sequelae and behavioral deficits in AD. Besides, impaired adult neurogenesis in the hippocampus has experimentally been realized as an underlying cause of dementia regardless of neurodegeneration. Therefore, nourishing the neurogenic process in the hippocampus has been considered an effective therapeutic strategy to mitigate memory loss. In the physiological state, the Wnt pathway has been identified as a potent mitogenic generator in the hippocampal stem cell niche. However, downstream components of Wnt signaling have been noticed to be downregulated in AD brains. Resveratrol (RSV) is a potent Sirtuin1 (SIRT1) enhancer that facilitates neuroprotection and promotes neurogenesis in the hippocampus of the adult brain. While SIRT1 is an important positive regulator of Wnt signaling, ample reports indicate that RSV treatment strongly mediates the fate determination of stem cells through Wnt signaling. However, the possible therapeutic roles of RSV-mediated SIRT1 enhancement on the regulation of hippocampal neurogenesis and reversal of memory loss through the Wnt signaling pathway have not been addressed yet. Taken together, this review describes RSV-mediated effects on the regulation of hippocampal neurogenesis via the activation of SIRT1 in synergy with the Wnt signaling. Further, the article emphasizes a hypothesis that RSV treatment can provoke the activation of quiescent neural stem cells and prime their neurogenic capacity in the hippocampus via Wnt signaling in AD.

Treadmill exercise improves hippocampal neural plasticity and relieves cognitive deficits in a mouse model of epilepsy.

Epilepsy frequently leads to cognitive dysfunction and approaches to treatment remain limited. Although regular exercise effectively improves learning and memory functions across multiple neurological diseases, its application in patients with epilepsy remains controversial. Here, we adopted a 14-day treadmill-exercise paradigm in a pilocarpine injection-induced mouse model of epilepsy. Cognitive assays confirmed the improvement of object and spatial memory after endurance training, and electrophysiological studies revealed the maintenance of hippocampal plasticity as a result of physical exercise. Investigations of the mechanisms underlying this effect revealed that exercise protected parvalbumin interneurons, probably via the suppression of neuroinflammation and improved integrity of blood-brain barrier. In summary, this work identified a previously unknown mechanism through which exercise improves cognitive rehabilitation in epilepsy.

Spurious Autobiographical Memory of Psychosis: A Mechanistic Hypothesis for the Resolution, Persistence, and Recurrence of Positive Symptoms in Psychotic Disorders.

Psychotic disorders are complex disorders with multiple etiologies. While increased dopamine synthesis capacity has been proposed to underlie psychotic episodes, dopamine-independent processes are also involved (less responsive to dopamine receptor-blocking medications). The underlying mechanism(s) of the reduction in antipsychotic responsiveness over time, especially after repeated relapses, remain unclear. Despite the consistent evidence of dopamine overactivity and hippocampal volume loss in schizophrenia, few accounts have been provided based on the interactive effect of dopamine on hippocampal synapse plasticity mediating autobiographical memory processes. The present hypothesis builds upon previous works showing the potential effects of dopamine overactivity on hippocampal-mediated neuroplasticity underlying autobiographical memory, alongside known patterns of autobiographical memory dysfunction in psychosis. We propose that spurious autobiographical memory of psychosis (SAMP) produced during active psychosis may be a key mechanism mediating relapses and treatment non-responsiveness. In a hyperdopaminergic state, SAMP is expected to be generated at an increased rate during active psychosis. Similar to other memories, it will undergo assimilation, accommodation, and extinction processes. However, if SAMP fails to integrate with existing memory, a discontinuity in autobiographical memory may result. Inadequate exposure to normalizing experiences and hyposalience due to overmedication or negative symptoms may also impede the resolution of SAMP. Residual SAMP is hypothesized to increase the propensity for relapse and treatment non-responsiveness. Based on recent findings on the role of dopamine in facilitating hippocampal synapse plasticity and autobiographical memory formation, the SAMP hypothesis is consistent with clinical observations of DUP effects, including the repetition of contents in psychotic relapses as well as the emergence of treatment non-responsiveness after repeated relapses. Clinical implications of the hypothesis highlight the importance of minimizing active psychosis, integrating psychosis memory, avoiding over-medication, and fostering normalizing experiences.

GPER1 deficiency causes sex-specific dysregulation of hippocampal plasticity and cognitive function.

Estrogens regulate synaptic properties and influence hippocampus-related learning and memory via estrogen receptors, which include the G-protein-coupled estrogen receptor 1 (GPER1). Studying mice, in which the GPER1 gene is dysfunctional (GPER1-KO), we here provide evidence for sex-specific roles of GPER1 in these processes. GPER1-KO males showed reduced anxiety in the elevated plus maze, whereas the fear response ('freezing') was specifically increased in GPER1-KO females in a contextual fear conditioning paradigm. In the Morris water maze, spatial learning and memory consolidation was impaired by GPER1 deficiency in both sexes. Notably, in the females, spatial learning deficits and the fear response were more pronounced if mice were in a stage of the estrous cycle, in which E2 serum levels are high (proestrus) or rising (diestrus). On the physiological level, excitability at Schaffer collateral synapses in CA1 increased in GPER1-deficient males and in proestrus/diestrus ('E2 high') females, concordant with an increased hippocampal expression of the AMPA-receptor subunit GluA1 in GPER1-KO males and females as compared to wildtype males. Further changes included an augmented early long-term potentiation (E-LTP) maintenance specifically in GPER1-KO females and an increased hippocampal expression of spinophilin in metestrus/estrus ('E2 low') GPER1-KO females. Our findings suggest modulatory and sex-specific functions of GPER1 in the hippocampal network, which reduce rather than increase neuronal excitability. Dysregulation of these functions may underlie sex-specific cognitive deficits or mood disorders.