Hippocampus Prefrontal Cortex Research Articles

Disrupted Hippocampal-Prefrontal Networks in a Rat Model of Fragile X Syndrome: A Study Linking Neural Dynamics to Autism-Like Behavioral Impairments.

FMR-KO and control rats underwent a battery of behavioral tests assessing sociability, memory, and anxiety. Single-unit electrophysiology recordings were then conducted to measure patterns of neural activity in H-PFC circuit. Advanced mathematical models were used to characterize the patterns that were then compared between groups using generalized linear mixed models. FMR-KO rats demonstrated significant behavioral deficits in sociability, spatial learning, and anxiety, aligning with symptoms of ASD. At the neural level, these rats exhibited abnormal firing patterns in the H-PFC circuit that is critical for learning, memory, and social behavior. The neural networks in FMR-KO rats were also less densely connected and more fragmented, particularly in hippocampal-PFC correlated firing. These findings suggest that disruptions in neural network dynamics underlie the observed behavioral impairments in FMR-KO rats. FMR-KO significantly disrupts several characteristics of action potential firing in the H-PFC network, leading to deficits in social behavior, memory, and anxiety, as seen in FXS. This disruption is characterized by less organized and less resilient hippocampal-PFC networks. These findings suggest that therapeutic strategies aimed at normalizing neural dynamics, such as with brain stimulation, could potentially improve behavior and cognitive functions in autistic individuals. Fragile X Syndrome is associated with autism, cognitive challenges and anxietyThe loss of Fmr1 protein disrupts processes involved in building neural networksThe consequence is abnormal neural dynamics in hippocampal-prefrontal cortex networksNormalization of dynamics could improve outcomes in FXS and ASD.

Dysfunctional hippocampal-prefrontal network underlies a multidimensional neuropsychiatric phenotype following early-life seizure.

Brain disturbances during development can have a lasting impact on neural function and behavior. Seizures during this critical period are linked to significant long-term consequences such as neurodevelopmental disorders, cognitive impairments, and psychiatric symptoms, resulting in a complex spectrum of multimorbidity. The hippocampus-prefrontal cortex (HPC-PFC) circuit emerges as a potential common link between such disorders. However, the mechanisms underlying these outcomes and how they relate to specific behavioral alterations are unclear. We hypothesized that specific dysfunctions of hippocampal-cortical communication due to early-life seizure would be associated with distinct behavioral alterations observed in adulthood. Here, we performed a multilevel study to investigate behavioral, electrophysiological, histopathological, and neurochemical long-term consequences of early-life Status epilepticus in male rats. We show that adult animals submitted to early-life seizure (ELS) present working memory impairments and sensorimotor disturbances, such as hyperlocomotion, poor sensorimotor gating, and sensitivity to psychostimulants despite not exhibiting neuronal loss. Surprisingly, cognitive deficits were linked to an aberrant increase in the HPC-PFC long-term potentiation (LTP) in a U-shaped manner, while sensorimotor alterations were associated with heightened neuroinflammation, as verified by glial fibrillary acidic protein (GFAP) expression, and altered dopamine neurotransmission. Furthermore, ELS rats displayed impaired HPC-PFC theta-gamma coordination and an abnormal brain state during active behavior resembling rapid eye movement (REM) sleep oscillatory dynamics. Our results point to impaired HPC-PFC functional connectivity as a possible pathophysiological mechanism by which ELS can cause cognitive deficits and psychiatric-like manifestations even without neuronal loss, bearing translational implications for understanding the spectrum of multidimensional developmental disorders linked to early-life seizures.

Dysfunctional hippocampal-prefrontal network underlies a multidimensional neuropsychiatric phenotype following early-life seizure

Brain disturbances during development can have a lasting impact on neural function and behavior. Seizures during this critical period are linked to significant long-term consequences such as neurodevelopmental disorders, cognitive impairments, and psychiatric symptoms, resulting in a complex spectrum of multimorbidity. The hippocampus-prefrontal cortex (HPC-PFC) circuit emerges as a potential common link between such disorders. However, the mechanisms underlying these outcomes and how they relate to specific behavioral alterations are unclear. We hypothesized that specific dysfunctions of hippocampal-cortical communication due to early-life seizure would be associated with distinct behavioral alterations observed in adulthood. Here, we performed a multilevel study to investigate behavioral, electrophysiological, histopathological, and neurochemical long-term consequences of early-life Status epilepticus in male rats. We show that adult animals submitted to early-life seizure (ELS) present working memory impairments and sensorimotor disturbances, such as hyperlocomotion, poor sensorimotor gating, and sensitivity to psychostimulants despite not exhibiting neuronal loss. Surprisingly, cognitive deficits were linked to an aberrant increase in the HPC-PFC long-term potentiation (LTP) in a U-shaped manner, while sensorimotor alterations were associated with heightened neuroinflammation, as verified by glial fibrillary acidic protein (GFAP) expression, and altered dopamine neurotransmission. Furthermore, ELS rats displayed impaired HPC-PFC theta-gamma coordination and an abnormal brain state during active behavior resembling rapid eye movement (REM) sleep oscillatory dynamics. Our results point to impaired HPC-PFC functional connectivity as a possible pathophysiological mechanism by which ELS can cause cognitive deficits and psychiatric-like manifestations even without neuronal loss, bearing translational implications for understanding the spectrum of multidimensional developmental disorders linked to early-life seizures.

Enhanced low-gamma band power in the hippocampus and prefrontal cortex in a rat model of depression is reversed by orexin-1 receptor antagonism

The hippocampal-prefrontal cortex network dynamics is reported to be involved in various cognitive functions and in different mood disturbances including depression. It has been suggested that blocking orexin-1 receptors can be beneficial in depression. The purpose of this study is to determine whether orexin-1 receptor antagonists have an impact on changes in brain oscillations in the hippocampus and prefrontal cortex in a rat model of depression. Forty-eight male Wistar rats were divided into six experimental groups: control, chronic mild stress (CMS), acute SB-334867, a selective orexin-1 receptor antagonist, treated rats (SB), chronic SB-treated (CSB), CMS+SB, and CMS+CSB. Two stainless steel recording electrodes were placed in the coordinates of the hippocampus (HPC) and the prefrontal cortex (PFC). After behavioral verification of the model, local field potentials were recorded at 1 kHz sampling frequency. The absolute power of different frequency bands was obtained using the Fast Fourier Transform (FFT) function, and the power spectral density (PSD) of each frequency band was calculated for each animal. In the CMS- treated animals, the low-gamma band power increased both in the HPC and PFC (p ≤ 0.05), which were reversed by chronic SB-334867 treatment (p ≤ 0.05). The alterations in theta, and high-gamma band power were not significant in CMS treated rats, while acute and chronic SB-334867 treatment diminished the theta and high-gamma band power (p ≤ 0.05), respectively. The hippocampal-prefrontal coherence decreased in the delta (p ≤ 0.01), theta (p ≤ 0.01), and alpha (p ≤ 0.05) band range of the CMS exposed rats. It is concluded that CMS boosts the low-gamma band power, which is reversed by CSB treatment. The low-frequency band coherence is attenuated after CMS treatment.

Alcohol-induced damage to the fimbria/fornix reduces hippocampal-prefrontal cortex connection during early abstinence

IntroductionAlcohol dependence is characterized by a gradual reduction in cognitive control and inflexibility to contingency changes. The neuroadaptations underlying this aberrant behavior are poorly understood. Using an animal model of alcohol use disorders (AUD) and complementing diffusion-weighted (dw)-MRI with quantitative immunohistochemistry and electrophysiological recordings, we provide causal evidence that chronic intermittent alcohol exposure affects the microstructural integrity of the fimbria/fornix, decreasing myelin basic protein content, and reducing the effective communication from the hippocampus (HC) to the prefrontal cortex (PFC). Using a simple quantitative neural network model, we show how disturbed HC-PFC communication may impede the extinction of maladaptive memories, decreasing flexibility. Finally, combining dw-MRI and psychometric data in AUD patients, we discovered an association between the magnitude of microstructural alteration in the fimbria/fornix and the reduction in cognitive flexibility. Overall, these findings highlight the vulnerability of the fimbria/fornix microstructure in AUD and its potential contribution to alcohol pathophysiology.SummaryFimbria vulnerability to alcohol underlies hippocampal-prefrontal cortex dysfunction and correlates with cognitive impairment.

Brain region-specific synaptic function of FUS underlies the FTLD-linked behavioural disinhibition.

Synaptic dysfunction is one of the earliest pathological processes that contribute to the development of many neurological disorders, including Alzheimer's disease and frontotemporal lobar degeneration. However, the synaptic function of many disease-causative genes and their contribution to the pathogenesis of the related diseases remain unclear. In this study, we investigated the synaptic role of fused in sarcoma, an RNA-binding protein linked to frontotemporal lobar degeneration and amyotrophic lateral sclerosis, and its potential pathological role in frontotemporal lobar degeneration using pyramidal neuron-specific conditional knockout mice (FuscKO). We found that FUS regulates the expression of many genes associated with synaptic function in a hippocampal subregion-specific manner, concomitant with the frontotemporal lobar degeneration-linked behavioural disinhibition. Electrophysiological study and molecular pathway analyses further reveal that fused in sarcoma differentially regulates synaptic and neuronal properties in the ventral hippocampus and medial prefrontal cortex, respectively. Moreover, fused in sarcoma selectively modulates the ventral hippocampus-prefrontal cortex projection, which is known to mediate the anxiety-like behaviour. Our findings unveil the brain region- and synapse-specific role of fused in sarcoma, whose impairment might lead to the emotional symptoms associated with frontotemporal lobar degeneration.

Longitudinal Trajectories of Memory Performance in Patients with Early-Stage Breast Cancer.

Background While breast cancer and its treatments may affect cognition, the longitudinal trajectories of cognition among those receiving differing cancer treatment types remain poorly understood. Prior research suggests hippocampal-prefrontal cortex network integrity may influence cognition, although how this network predicts performance over time remains unclear. Methods We conducted a prospective trial including 69 patients with early-stage breast cancer receiving adjuvant therapy and 12 controls. Longitudinal cognitive testing was conducted at four visits: pretreatment-baseline, 6-7 months, 14-15 months, and 23-24 months. Cognitive composite scores of episodic memory, executive functioning, and processing speed were assessed at each timepoint. Baseline structural MRI was obtained in a subset of these participants, and hippocampal and prefrontal cortex regional volumes were extracted. Results Longitudinal linear mixed modeling revealed significant group by time interactions on memory performance, controlling for age and education. Post hoc analyses revealed this effect was driven by patients treated with chemotherapy or chemotherapy plus hormone therapy, who demonstrated the least improvement in memory scores over time. Treatment group did not significantly influence the relationship between time and processing speed or executive functioning. Neither pretreatment hippocampal nor prefrontal volume differed between groups, and there were no significant group by time by baseline regional volume effects on cognition. Conclusion Patients with early-stage breast cancer treated with chemotherapy or chemotherapy plus hormone therapy benefit less from practice effects seen in healthy controls on memory tests. Loss of longitudinal practice effect may be a new and clinically relevant measure for capturing patients' experience of cognitive difficulties after treatment.

Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile.

Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8–9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.

Transcerebral information coordination in directional hippocampus-prefrontal cortex network during working memory based on bimodal neural electrical signals.

Working memory (WM) is a kind of advanced cognitive function, which requires the participation and cooperation of multiple brain regions. Hippocampus and prefrontal cortex are the main responsible brain regions for WM. Exploring information coordination between hippocampus and prefrontal cortex during WM is a frontier problem in cognitive neuroscience. In this paper, an advanced information theory analysis based on bimodal neural electrical signals (local field potentials, LFPs and spikes) was employed to characterize the transcerebral information coordination across the two brain regions. Firstly, LFPs and spikes were recorded simultaneously from rat hippocampus and prefrontal cortex during the WM task by using multi-channel in vivo recording technique. Then, from the perspective of information theory, directional hippocampus-prefrontal cortex networks were constructed by using transfer entropy algorithm based on spectral coherence between LFPs and spikes. Finally, transcerebral coordination of bimodal information at the brain-network level was investigated during acquisition and performance of the WM task. The results show that the transfer entropy in directional hippocampus-prefrontal cortex networks is related to the acquisition and performance of WM. During the acquisition of WM, the information flow, local information transmission ability and information transmission efficiency of the directional hippocampus-prefrontal networks increase over learning days. During the performance of WM, the transfer entropy from the hippocampus to prefrontal cortex plays a leading role for bimodal information coordination across brain regions and hippocampus has a driving effect on prefrontal cortex. Furthermore, bimodal information coordination in the hippocampus → prefrontal cortex network could predict WM during the successful performance of WM.

The anxiety-specific hippocampus-prefrontal cortex pathways links to procrastination through self-control.

Procrastination, which is defined as delaying an intended course of action despite negative outcomes, is demonstrated to have a deal with negative emotion including trait anxiety. Although highly anxious individuals showed impoverished control ability, no studies have indicated the role of self‐control in the relationship between trait anxiety and procrastination, and its neural correlates. To this end, we used the sliding window method to calculate the temporal deviation of dynamic functional connectivity (FC) in 312 healthy participants who underwent the resting‐state functional magnetic resonance imaging (fMRI) scanning. In line with our hypothesis, higher trait anxiety is linked to more procrastination via poorer self‐control. Besides, the dynamic FC analyses showed that trait anxiety was positively correlated with dynamic FC variability in hippocampus–prefrontal cortex (HPC–PFC) pathways, including left rostral hippocampus–left superior frontal gyrus (left rHPC–left SFG), and left rHPC–right middle frontal gyrus (left rHPC–‐MFG). Furthermore, the structural equation modeling (SEM) uncovered a mediated role of self‐control in the association between the anxiety‐specific brain connectivity and procrastination. These findings suggest that the HPC–PFC pathways may reflect impoverished regulatory ability over the negative thoughts for anxious individuals, and thereby incurs more procrastination, which enhances our understanding of how trait anxiety links to procrastination.

Neuromodulation of Hippocampal-Prefrontal Cortical Synaptic Plasticity and Functional Connectivity: Implications for Neuropsychiatric Disorders.

The hippocampus-prefrontal cortex (HPC-PFC) pathway plays a fundamental role in executive and emotional functions. Neurophysiological studies have begun to unveil the dynamics of HPC-PFC interaction in both immediate demands and long-term adaptations. Disruptions in HPC-PFC functional connectivity can contribute to neuropsychiatric symptoms observed in mental illnesses and neurological conditions, such as schizophrenia, depression, anxiety disorders, and Alzheimer’s disease. Given the role in functional and dysfunctional physiology, it is crucial to understand the mechanisms that modulate the dynamics of HPC-PFC communication. Two of the main mechanisms that regulate HPC-PFC interactions are synaptic plasticity and modulatory neurotransmission. Synaptic plasticity can be investigated inducing long-term potentiation or long-term depression, while spontaneous functional connectivity can be inferred by statistical dependencies between the local field potentials of both regions. In turn, several neurotransmitters, such as acetylcholine, dopamine, serotonin, noradrenaline, and endocannabinoids, can regulate the fine-tuning of HPC-PFC connectivity. Despite experimental evidence, the effects of neuromodulation on HPC-PFC neuronal dynamics from cellular to behavioral levels are not fully understood. The current literature lacks a review that focuses on the main neurotransmitter interactions with HPC-PFC activity. Here we reviewed studies showing the effects of the main neurotransmitter systems in long- and short-term HPC-PFC synaptic plasticity. We also looked for the neuromodulatory effects on HPC-PFC oscillatory coordination. Finally, we review the implications of HPC-PFC disruption in synaptic plasticity and functional connectivity on cognition and neuropsychiatric disorders. The comprehensive overview of these impairments could help better understand the role of neuromodulation in HPC-PFC communication and generate insights into the etiology and physiopathology of clinical conditions.

Asymmetric Frequency-Specific Feedforward and Feedback Information Flow between Hippocampus and Prefrontal Cortex during Verbal Memory Encoding and Recall.

Hippocampus and prefrontal cortex (PFC) circuits are thought to play a prominent role in human episodic memory, but the precise nature, and electrophysiological basis, of directed information flow between these regions and their role in verbal memory formation has remained elusive. Here we investigate nonlinear causal interactions between hippocampus and lateral PFC using intracranial EEG recordings (26 participants, 16 females) during verbal memory encoding and recall tasks. Direction-specific information theoretic analysis revealed higher causal information flow from the hippocampus to PFC than in the reverse direction. Crucially, this pattern was observed during both memory encoding and recall, and the strength of causal interactions was significantly greater during memory task performance than resting baseline. Further analyses revealed frequency specificity of interactions with greater causal information flow from hippocampus to the PFC in the delta-theta frequency band (0.5-8 Hz); in contrast, PFC to hippocampus causal information flow were stronger in the beta band (12-30 Hz). Across all hippocampus-PFC electrode pairs, propagation delay between the source and target signals was estimated to be 17.7 ms, which is physiologically meaningful and corresponds to directional signal interactions on a timescale consistent with monosynaptic influence. Our findings identify distinct asymmetric feedforward and feedback signaling mechanisms between the hippocampus and PFC and their dissociable roles in memory recall, demonstrate that these regions preferentially use different frequency channels, and provide novel insights into the electrophysiological basis of directed information flow during episodic memory formation in the human brain.SIGNIFICANCE STATEMENT Hippocampal-PFC circuits play a critical role in episodic memory in rodents, nonhuman primates, and humans. Investigations using noninvasive fMRI techniques have provided insights into coactivation of the hippocampus and PFC during memory formation; however, the electrophysiological basis of dynamic causal hippocampal-PFC interactions in the human brain is poorly understood. Here, we use data from a large cohort of intracranial EEG recordings to investigate the neurophysiological underpinnings of asymmetric feedforward and feedback hippocampal-PFC interactions and their nonlinear causal dynamics during both episodic memory encoding and recall. Our findings provide novel insights into the electrophysiological basis of directed bottom-up and top-down information flow during episodic memory formation in the human brain.

Methoxphenidine (MXP) induced abnormalities: Addictive and schizophrenia‐related behaviours based on an imbalance of neurochemicals in the brain

Methoxphenidine is a dissociative-based novel psychoactive designer drug. Although fatal accidents from methoxphenidine abuse have been reported, recreational use of the drug continues. We aim to provide scientific supportfor legal regulation of recreational abuse of methoxphenidine by demonstrating its the pharmacological action. Addictive potential of methoxphenidine was examined using intravenous self-administration test with rats and conditioned place preference test with mice. Further, a series of behavioural tests (open field test, elevated plus maze test, novel object recognition test, social interaction test and tail suspension test) performed to assess whether methoxphenidine caused schizophrenia-related symptoms in mice. Additionally, neurotransmitter enzyme-linked immunosorbent assay and western blot were used to confirm methoxphenidine-induced neurochemical changes in specific brain regions related to abnormal behaviours. Methoxphenidine caused addictive behaviours via reinforcing and rewarding effects. Consistently, methoxphenidine induced over-activation of dopamine pathways in the nuclear accumbens, indicating activation of the brain reward circuit. Also, methoxphenidine caused all categories of schizophrenia-related symptoms, including positive symptoms (hyperactivity, impulsivity), negative symptoms (anxiety, social withdrawal, depression) and cognitive impairment. Consistently, methoxphenidine led to the disruption of the hippocampal-prefrontal cortex pathway that is considered to be pathological involved in schizophrenia. We demonastrate that methoxphenidine causes addictive and schizophrenia-like behaviours and induces neurochemical changes in brain regions associated with these behaviours. We propose that methoxphenidine could be used in developing useful animal disease models and that it also requires legal restrictions on its recreational use.

Chronic Low Dose Neutron Exposure Results in Altered Neurotransmission Properties of the Hippocampus-Prefrontal Cortex Axis in Both Mice and Rats.

The proposed deep space exploration to the moon and later to Mars will result in astronauts receiving significant chronic exposures to space radiation (SR). SR exposure results in multiple neurocognitive impairments. Recently, our cross-species (mouse/rat) studies reported impaired associative memory formation in both species following a chronic 6-month low dose exposure to a mixed field of neutrons (1 mGy/day for a total dose pf 18 cGy). In the present study, we report neutron exposure induced synaptic plasticity in the medial prefrontal cortex, accompanied by microglial activation and significant synaptic loss in the hippocampus. In a parallel study, neutron exposure was also found to alter fluorescence assisted single synaptosome LTP (FASS-LTP) in the hippocampus of rats, that may be related to a reduced ability to insert AMPAR into the post-synaptic membrane, which may arise from increased phosphorylation of the serine 845 residue of the GluA1 subunit. Thus, we demonstrate for the first time, that low dose chronic neutron irradiation impacts homeostatic synaptic plasticity in the hippocampal-cortical circuit in two rodent species, and that the ability to successfully encode associative recognition memory is a dynamic, multicircuit process, possibly involving compensatory changes in AMPAR density on the synaptic surface.

Nucleus Reuniens Lesion and Antidepressant Treatment Prevent Hippocampal Neurostructural Alterations Induced by Chronic Mild Stress in Male Rats

The hippocampus-prefrontal cortex circuit plays a major role in stress and in the neurobiology of depression and its treatment. Disruption of this circuit by lesioning the thalamic nucleus reuniens (RE) has been shown to prevent the detrimental effects of chronic mild stress on prefrontal cortex neuroplasticity indices in male rats. However, it remains unknown whether hippocampal neurostructural response to stress is modified by RE lesion. In the present study, adult male rats were subjected to the chronic mild stress model of depression and were treated with either vehicle or an antidepressant (i.e. sertraline). Moreover, a group of animals was subjected to RE lesion before stress exposure with or without sertraline treatment. We demonstrated that chronic mild stress induced hippocampal CA1 dendritic atrophy and this was prevented by pre-stress RE lesion to the same extent that antidepressant treatment reversed it. The present findings highlight the importance of hippocampal-prefrontal cortex communication in chronic stress effects on hippocampal neuroplasticity and contribute to the elucidation of the role of RE in neurostructural changes underlying stress-driven depression and its treatment.

Long-term potentiation prevents ketamine-induced aberrant neurophysiological dynamics in the hippocampus-prefrontal cortex pathway in vivo

N-methyl-D-aspartate receptor (NMDAr) antagonists such as ketamine (KET) produce psychotic-like behavior in both humans and animal models. NMDAr hypofunction affects normal oscillatory dynamics and synaptic plasticity in key brain regions related to schizophrenia, particularly in the hippocampus and the prefrontal cortex. It has been shown that prior long-term potentiation (LTP) occluded the increase of synaptic efficacy in the hippocampus-prefrontal cortex pathway induced by MK-801, a non-competitive NMDAr antagonist. However, it is not clear whether LTP could also modulate aberrant oscillations and short-term plasticity disruptions induced by NMDAr antagonists. Thus, we tested whether LTP could mitigate the electrophysiological changes promoted by KET. We recorded HPC-PFC local field potentials and evoked responses in urethane anesthetized rats, before and after KET administration, preceded or not by LTP induction. Our results show that KET promotes an aberrant delta-high-gamma cross-frequency coupling in the PFC and an enhancement in HPC-PFC evoked responses. LTP induction prior to KET attenuates changes in synaptic efficiency and prevents the increase in cortical gamma amplitude comodulation. These findings are consistent with evidence that increased efficiency of glutamatergic receptors attenuates cognitive impairment in animal models of psychosis. Therefore, high-frequency stimulation in HPC may be a useful tool to better understand how to prevent NMDAr hypofunction effects on synaptic plasticity and oscillatory coordination in cortico-limbic circuits.

Glutamate dehydrogenase deficiency disrupts glutamate homeostasis in hippocampus and prefrontal cortex and impairs recognition memory.

Glutamate Dehydrogenase 1 (GDH), encoded by the Glud1 gene in rodents, is a mitochondrial enzyme critical for maintaining glutamate homeostasis at the tripartite synapse. Our previous studies indicate that the hippocampus may be particularly vulnerable to GDH deficiency in central nervous system (CNS). Here, we first asked whether mice with a homozygous deletion of Glud1 in CNS (CNS-Glud1 -/- mice) express different levels of glutamate in hippocampus, and found elevated glutamate as well as glutamine in dorsal and ventral hippocampus, and increased glutamine in medial prefrontal cortex (mPFC). l-serine and d-serine, which contribute to glutamate homeostasis and NMDA receptor function, are increased in ventral but not dorsal hippocampus, and in mPFC. Protein expression levels of the GABA synthesis enzyme glutamate decarboxylase (GAD) GAD67 were decreased in the ventral hippocampus as well. Behavioral analysis revealed deficits in visual, spatial and social novelty recognition abilities, which require intact hippocampal-prefrontal cortex circuitry. Finally, hippocampus-dependent contextual fear retrieval was deficient in CNS-Glud1 -/- mice, and c-Fos expression (indicative of neuronal activation) in the CA1 pyramidal layer was reduced immediately following this task. These data point to hippocampal subregion-dependent disruption in glutamate homeostasis and excitatory/inhibitory balance, and to behavioral deficits that support a decline in hippocampal-prefrontal cortex connectivity. Together with our previous data, these findings also point to different patterns of basal and activity-induced hippocampal abnormalities in these mice. In sum, GDH contributes to healthy hippocampal and PFC function; disturbed GDH function is relevant to several psychiatric and neurological disorders.

Development of Hippocampal-Prefrontal Cortex Interactions through Adolescence.

Significant improvements in cognitive control occur from childhood through adolescence, supported by the maturation of prefrontal systems. However, less is known about the neural basis of refinements in cognitive control proceeding from adolescence to adulthood. Accumulating evidence indicates that integration between hippocampus (HPC) and prefrontal cortex (PFC) supports flexible cognition and has a protracted neural maturation. Using a longitudinal design (487 scans), we characterized developmental changes from 8 to 32years of age in HPC-PFC functional connectivity at rest and its associations with cognitive development. Results indicated significant increases in functional connectivity between HPC and ventromedial PFC (vmPFC), but not dorsolateral PFC. Importantly, HPC-vmPFC connectivity exclusively predicted performance on the Stockings of Cambridge task, which probes problem solving and future planning. These data provide evidence that maturation of high-level cognition into adulthood is supported by increased functional integration across the HPC and vmPFC through adolescence.

An Exploratory Study of Exercise-related Effects on Memory and Hippocampal Connectivity in Schizophrenia.

Memory impairment in schizophrenia has been linked to abnormal functioning of fronto-temporal networks. In this pilot study, we investigated whether 12-weeks of exercise improved hippocampal-dependent memory functions and resting-state functional connectivity in middle-aged adults with schizophrenia. The exercise regimen was feasible, well-attended, and safe. There was a pre- to post-intervention increase in spatial memory accuracy that was correlated to an increase in hippocampal-prefrontal cortex connectivity. No increase was found in pattern separation performance or hippocampal volume. A controlled trial is needed to replicate these findings and elucidate the functional brain networks underlying exercise-induced cognitive improvement in schizophrenia.

The activity of thalamic nucleus reuniens is critical for memory retrieval, but not essential for the early phase of "off-line" consolidation.

Spatial navigation depends on the hippocampal function, but also requires bidirectional interactions between the hippocampus (HPC) and the prefrontal cortex (PFC). The cross-regional communication is typically regulated by critical nodes of a distributed brain network. The thalamic nucleus reuniens (RE) is reciprocally connected to both HPC and PFC and may coordinate the information flow within the HPC–PFC pathway. Here we examined if RE activity contributes to the spatial memory consolidation. Rats were trained to find reward following a complex trajectory on a crossword-like maze. Immediately after each of the five daily learning sessions the RE was reversibly inactivated by local injection of muscimol. The post-training RE inactivation affected neither the spatial task acquisition nor the memory retention, which was tested after a 20-d “forgetting” period. In contrast, the RE inactivation in well-trained rats prior to the maze exposure impaired the task performance without affecting locomotion or appetitive motivation. Our results support the role of the RE in memory retrieval and/or “online” processing of spatial information, but do not provide evidence for its engagement in “off-line” processing, at least within a time window immediately following learning experience.