Hippocampal Neural Activity Research Articles

TREM2 alleviates long-term cognitive dysfunction after subarachnoid hemorrhage in mice by attenuating hippocampal neuroinflammation via PI3K/Akt signaling pathway

Subarachnoid hemorrhage (SAH) often leads to long-term cognitive deficits in patients, particularly due to injury to brain regions such as the hippocampus. This study aims to investigate the role of the triggering receptor expressed on myeloid cells 2 (TREM2) in mitigating hippocampal injury and associated cognitive impairments following SAH. To explore the protective effects of TREM2, we utilized the TREM2 agonist COG1410 to upregulate TREM2 expression and employed TREM2 knockout (KO) mice to verify the necessity of TREM2 for this protective role. The study further examined the involvement of the PI3K/Akt signaling pathway in TREM2-mediated neuroprotection. Our findings indicate that the upregulation of TREM2 significantly alleviated long-term cognitive deficits and promoted the recovery of hippocampal neural activity post-SAH. The neuroprotective effects were linked to reduced microglial activation and decreased secretion of inflammatory factors within the hippocampus. In contrast, TREM2 KO mice did not exhibit these protective effects. Furthermore, inhibition of the PI3K/Akt pathway also diminished these protective effects of TREM2 upregulation and worsened cognitive outcomes. In conclusion, TREM2 upregulation mitigates long-term cognitive dysfunction following SAH by attenuating hippocampal neuroinflammation via the PI3K/Akt signaling pathway. These findings suggest that TREM2 could be a potential therapeutic target for improving cognitive outcomes after SAH.

The translational inhibitor and amnestic agent emetine also suppresses ongoing hippocampal neural activity similarly to other blockers of protein synthesis.

The consolidation of memory is thought to ultimately depend on the synthesis of new proteins, since translational inhibitors such as anisomycin and cycloheximide adversely affect the permanence of long-term memory. However, when applied directly in brain, these agents also profoundly suppress neural activity to an extent that is directly correlated to the degree of protein synthesis inhibition caused. Given that neural activity itself is likely to help mediate consolidation, this finding is a serious criticism of the strict de novo protein hypothesis of memory. Here, we test the neurophysiological effects of another translational inhibitor, emetine. Unilateral intra-hippocampal infusion of emetine suppressed ongoing local field and multiunit activity at ipsilateral sites as compared to the contralateral hippocampus in a fashion that was positively correlated to the degree of protein synthesis inhibition as confirmed by autoradiography. This suppression of activity was also specific to the circumscribed brain region in which protein synthesis inhibition took place. These experiments provide further evidence that ongoing protein synthesis is necessary and fundamental for neural function and suggest that the disruption of memory observed in behavioral experiments using translational inhibitors may be due, in large part, to neural suppression.

Correlation between desynchrony of hippocampal neural activity and hyperlocomotion in the model mice of schizophrenia and therapeutic effects of aripiprazole.

The hippocampus has been reported to be morphologically and neurochemically altered in schizophrenia (SZ). Hyperlocomotion is a characteristic SZ-associated behavioral phenotype, which is associated with dysregulated dopamine system function induced by hippocampal hyperactivity. However, the neural mechanism of hippocampus underlying hyperlocomotion remains largely unclear. Mouse pups were injected with N-methyl-D-aspartate receptor antagonist (MK-801) or vehicle twice daily on postnatal days (PND) 7-11. In the adulthood phase, one cohort of mice underwent electrode implantation in field CA1 of the hippocampus for the recording local field potentials and spike activity. A separate cohort of mice underwent surgery to allow for calcium imaging of the hippocampus while monitoring the locomotion. Lastly, the effects of atypical antipsychotic (aripiprazole, ARI) were evaluated on hippocampal neural activity. We found that the hippocampal theta oscillations were enhanced in MK-801-treated mice, but the correlation coefficient between the hippocampal spiking activity and theta oscillation was reduced. Consistently, although the rate and amplitude of calcium transients of hippocampal neurons were increased, their synchrony and correlation to locomotion speed were disrupted. ARI ameliorated perturbations produced by the postnatal MK-801 treatment. These results suggest that the disruption of neural coordination may underly the neuropathological mechanism for hyperlocomotion of SZ.

Corticosteroid Treatment During Sepsis Alters Hippocampal Function in Male and Female Survivors

BackgroundMillions of sepsis survivors annually face neuropsychiatric sequelae of their illness. Corticosteroids are frequently administered for sepsis, and their use improves neuropsychiatric outcomes, but the mechanisms are unknown. In light of prior work that has shown persistent inflammation in sepsis survivors, we hypothesized that short-term corticosteroid treatment during illness would reverse the long-term impact of sepsis on inflammatory gene expression in the hippocampus and rescue associated changes to affective behaviors. MethodsMale and female mice underwent cecal ligation and puncture or a sham surgery to induce acute infection and were treated for 5 days with corticosterone or vehicle. Starting 2 weeks after the surgery, we performed functional phenotyping in the survivor mice followed by hippocampal RNA sequencing to identify underlying mechanisms. ResultsLong-term cecal ligation and puncture survivors exhibited anxiety-like behavior, increased central hypothalamic-pituitary-adrenal axis activity, and persistent systemic and neuroinflammation. Corticosterone treatment during illness did not reverse anxiety-like behavior or inflammation in survivors. Instead, corticosterone treatment impaired object memory and increased active coping behavior in females. History of corticosterone treatment influenced the expression of >10% of detectable transcripts in the dorsal and ventral hippocampus, including a coordinated downregulation of activity-dependent genes. ConclusionsCorticosterone treatment during sepsis impaired memory formation in survivors and caused a lasting decrease in hippocampal neural activity, which could underlie its effect on memory. Future studies should focus on how this lasting effect of corticosteroid treatment on hippocampal activity and memory translates into improved neuropsychiatric outcomes in human sepsis survivors.

Transcranial ultrasound stimulation modulates neural activities during NREM and REM depending on the stimulation phase of slow oscillations and theta waves in the hippocampus.

Modulation of the hippocampal neural activity by low-intensity transcranial ultrasound stimulation depends on the phase of theta rhythm and can also regulate sleep rhythm. However, until now, the modulatory effect of ultrasound stimulation on neural activity in different sleep states depending on the phase of local field potential stimulation in the hippocampus was unclear. To answer this question, closed-loop ultrasound stimulation was applied to in-phase (upstate)/out-of-phase slow oscillations in the hippocampus during non-rapid eye movement sleep, and to the peaks and troughs of theta oscillations in the hippocampus during wake in a mouse model. Local field potential of the hippocampus within 3-h after the ultrasound stimulation during light-on sleep cycle was recorded. We found that (i) under slow-oscillation in-phase stimulation, ultrasound stimulation upregulated the non-rapid eye movement ratio and decreased the wake ratio. Furthermore, it increased the ripple density during non-rapid eye movement and enhanced the coupling of the spindle-ripple during non-rapid eye movement as well as the theta-high gamma phase-amplitude coupling during the REM period. In addition, theta during the REM period showed a more stable oscillation mode. (ii) Under slow-oscillation out-of-phase stimulation, ultrasound stimulation increased the density of ripple during non-rapid eye movement and enhanced the theta-high gamma phase-amplitude coupling strength during REM. Furthermore, theta oscillations during REM were significantly slower and showed higher variability. (iii) Under the phase-locked peak and trough stimulation of theta oscillation, ultrasound stimulation increased the ripple density during non-rapid eye movement, weakened the coupling strength of spindle-ripple during non-rapid eye movement, and enhanced theta-high gamma phase-amplitude coupling during REM. However, theta oscillation mode was not changed significantly during REM. The above results suggest that the regulatory effect of ultrasound stimulation on neural activity in different sleep states depends on the stimulation phases of slow oscillations and theta waves in the hippocampus.

The transcriptional co‐activator Yap1 promotes adult hippocampal neural stem cell activation

Most adult hippocampal neural stem cells (NSCs) remain quiescent, with only a minor portion undergoing active proliferation and neurogenesis. The molecular mechanisms that trigger the transition from quiescence to activation are still poorly understood. Here, we found the activity of the transcriptional co‐activator Yap1 to be enriched in active NSCs. Genetic deletion of Yap1 led to a significant reduction in the relative proportion of active NSCs, supporting a physiological role of Yap1 in regulating the transition from quiescence to activation. Overexpression of wild‐type Yap1 in adult NSCs did not induce NSC activation, suggesting tight upstream control mechanisms, but overexpression of a gain‐of‐function mutant (Yap1‐5SA) elicited cell cycle entry in NSCs and hilar astrocytes. Consistent with a role of Yap1 in NSC activation, single cell RNA sequencing revealed a partial induction of an activated NSC gene expression program. Furthermore, Yap1‐5SA expression also induced expression of Taz and other key components of the Yap/Taz regulon that were previously identified in glioblastoma stem cell‐like cells. Consequently, dysregulated Yap1 activity led to repression of hippocampal neurogenesis, aberrant cell differentiation, and partial acquisition of a glioblastoma stem cell‐like signature.

Effect of low-intensity transcranial ultrasound stimulation on theta and gamma oscillations in the mouse hippocampal CA1.

Previous studies have demonstrated that low-intensity transcranial ultrasound stimulation (TUS) can eliminate hippocampal neural activity. However, until now, it has remained unclear how ultrasound modulates theta and gamma oscillations in the hippocampus under different behavioral states. In this study, we used ultrasound to stimulate the CA1 in mice in anesthesia, awake and running states, and we simultaneously recorded the local field potential of the stimulation location. We analyzed the power spectrum, phase-amplitude coupling (PAC) of theta and gamma oscillations, and their relationship with ultrasound intensity. The results showed that (i) TUS significantly enhanced the absolute power of theta and gamma oscillations under anesthesia and in the awake state. (ii) The PAC strength between theta and gamma oscillations is significantly enhanced under the anesthesia and awake states but is weakened under the running state with TUS. (iii) Under anesthesia, the relative power of theta decreases and that of gamma increases as ultrasound intensity increases, and the result under the awake state is opposite that under the anesthesia state. (iv) The PAC index between theta and gamma increases as ultrasound intensity increases under the anesthesia and awake states. The above results demonstrate that TUS can modulate theta and gamma oscillations in the CA1 and that the modulation effect depends on behavioral states. Our study provides guidance for the application of ultrasound in modulating hippocampal function.

Effect of stimulation frequency on hippocampal electric field induced by deep-brain magnetic stimulation

Deep-brain Magnetic Stimulation (DMS) is a noninvasive brain modulation method that improves hippocampal neural activity. The frequency of DMS has a significant effect on the hippocampal induced electric field. In this paper, we investigate the relationship between stimulation frequency and DMS-induced hippocampal electric field. The frequency sensitivity and distribution uniformity of the hippocampal electric field are calculated to quantify this relationship. The results show that the DMS-induced hippocampal electric field has a frequency-dependent property. The frequency sensitivity of the DMS-induced hippocampal electric field in the high frequency band is lower than that in the low frequency band, which corresponds to the low-pass filtering property of the neuron membrane. The frequency sensitivity of DMS-induced hippocampal electric field is highest in the range of 30–40 Hz. The uniformity of the hippocampal electric field induced by a single coil also reaches the highest in the range of 30–40 Hz, while uniformity of the hippocampal electric field induced by multiple-coil increases with increasing frequency. The frequency-dependent property of the DMS-induced hippocampal electric field is positively correlated with the quantity and size of coils, while negatively correlated with the spacing of the coils. This study is of great help in the selection of DMS frequencies and the design of coils.

Multimodal Brain MRI of Deep Gray Matter Changes Associated With Inflammatory Bowel Disease.

Behavioral symptoms, including mood disorders, substantially impact the quality of life of patients with inflammatory bowel disease (IBD), even when clinical remission is achieved. Here, we used multimodal magnetic resonance imaging (MRI) to determine if IBD is associated with changes in the structure and function of deep gray matter brain regions that regulate and integrate emotional, cognitive, and stress responses. Thirty-five patients with ulcerative colitis (UC) or Crohn's disease (CD) and 32 healthy controls underwent 3 Tesla MRIs to assess volume, neural activity, functional connection strength (connectivity), inflammation, and neurodegeneration of key deep gray matter brain regions (thalamus, caudate, pallidum, putamen, amygdala, hippocampus, and hypothalamus) involved in emotional, cognitive and stress processing. Associations with sex, presence of pain, disease activity, and C-reactive protein (CRP) concentration were examined. Significantly increased activity and functional connectivity were observed in cognitive and emotional processing brain regions, including parts of the limbic system, basal ganglia, and hypothalamus of IBD patients compared with healthy controls. Inflammatory bowel disease patients exhibited significantly increased volumes of the amygdala and hypothalamus, as well as evidence of neurodegeneration in the putamen and pallidum. Hippocampal neural activity was increased in IBD patients with active disease. The volume of the thalamus was positively correlated with CRP concentration and was increased in females experiencing pain. Patients with IBD exhibit functional and structural changes in the limbic and striatal systems. These changes may be targets for assessing or predicting the response to therapeutic interventions aimed at improving comorbid emotional and cognitive symptoms.

Variations in the Value of Integrated Information Theory Estimated from Hippocampal Neural Activity During Acquisition of Operant Behavior in Rats

Variations in the Value of Integrated Information Theory Estimated from Hippocampal Neural Activity During Acquisition of Operant Behavior in Rats

Supramammillary regulation of locomotion and hippocampal activity.

Locomotor speed is a basic input used to calculate one’s position, but where this signal comes from is unclear. We identified neurons in the supramammillary nucleus (SuM) of the rodent hypothalamus that were highly correlated with future locomotor speed and reliably drove locomotion when activated. Robust locomotion control was specifically identified in Tac1 (substance P)–expressing (SuMTac1+) neurons, the activation of which selectively controlled the activity of speed-modulated hippocampal neurons. By contrast, Tac1-deficient (SuMTac1−) cells weakly regulated locomotion but potently controlled the spike timing of hippocampal neurons and were sufficient to entrain local network oscillations. These findings emphasize that the SuM not only regulates basic locomotor activity but also selectively shapes hippocampal neural activity in a manner that may support spatial navigation.

In vivo endocannabinoid dynamics at the timescale of physiological and pathological neural activity

The brain's endocannabinoid system is a powerful controller of neurotransmitter release, shaping synaptic communication under physiological and pathological conditions. However, our understanding of endocannabinoid signaling invivo is limited by the inability to measure their changes at timescales commensurate with the high lability of lipid signals, leaving fundamental questions of whether, how, and which endocannabinoids fluctuate with neural activity unresolved. Using novel imaging approaches in awake behaving mice, we now demonstrate that the endocannabinoid 2-arachidonoylglycerol, not anandamide, is dynamically coupled to hippocampal neural activity with high spatiotemporal specificity. Furthermore, we show that seizures amplify the physiological endocannabinoid increase by orders of magnitude and drive the downstream synthesis of vasoactive prostaglandins that culminate in a prolonged stroke-like event. These results shed new light on normal and pathological endocannabinoid signaling invivo.

Total sleep deprivation-induced electrophysiological activities changes in rat hippocampal CA1 detected by microelectrode arrays

Total sleep deprivation (TSD) produces impairments in cognitive on individuals. The measurement of rat hippocampal CA1 neural activity after TSD is of importance to understand the harmful effect induced by TSD on the cellular level. In this work, the deficit of spatial learning and memory maintenance caused by TSD was demonstrated in the Morris Water Maze test. And a novel 16-site micro-electrode array we designed and fabricated was successfully implanted into the target area of rat brain to measure the neuronal activities in rat hippocampal CA1 before and after TSD. The probe was successfully implanted into the target area of brain. The detection results showed that the neuronal firing of both Pyramidal neurons and interneurons in CA1 got elevated, and the fluctuation of local field potential (LFP) became more frequent after TSD, indicating that TSD exerted excitatory effects on CA1 neurons. Besides, the power of spike firing and LFP got significantly increased in low frequency band, especially theta band after TSD, accompanied by the increased occurrence of OFF period during spike firing. It is concluded that the disturbed theta activity induced by TSD in hippocampus was associated with the altered excitatory/inhibitory balance of neurons in the brain. And the increased occurrence of OFF period in neuronal firing after TSD disrupted the propagation of theta activity in the brain, which might partially explain the overall decline in spatial learning performance of rats.

Ligustilide enhances hippocampal neural stem cells activation to restore cognitive function in the context of postoperative cognitive dysfunction.

Ligustilide exerts potential neuroprotective effects against various cerebral ischaemic insults and neurodegenerative disorders. However, the function and mechanisms of LIG-mediated hippocampal neural stem cells (H-NSCs) activation as well as cognitive recovery in the context of post-operative cognitive dysfunction (POCD) remain elusive and need to be explored. Mice were subjected to transient global cerebral ischaemia and reperfusion (tGCI/R) injury and treated with LIG (80 mg/kg) or vehicle for 1month. Morris water maze test and western blot were employed to assess cognitive function. Nissl staining and immunofluorescence (IF) staining were used to detect H-NSCs proliferation and neurogenesis in hippocampus. Subsequently, primary H-NSCs were treated with LIG, and the level of H-NSCs proliferation and neuronal-differentiation was examined by IF staining for Edu and β-Tubulin III. The protein levels of ERK1/2, β-catenin, NICD, TLR4, Akt and FoxO1 were examined using western blotting. Finally, pretreatment with the ERK agonist SCH772984 was performed to observe the change in ERK expression. LIG treatment promoted H-NSCs proliferation and neurogenesis, increased the number of neurons in the hippocampal subfields, and ultimately reversed cognitive impairment in tGCI/R injury. Furthermore, LIG also promoted primary H-NSCs proliferation and neuronal-differentiation, as well as ERK1/2 phosphorylation. Pretreatment with SCH772984 effectively reversed the ability of LIG to induce ERK1/2 phosphorylation and promote H-NSCs proliferation and neuronal-differentiation. LIG can promote cognitive recovery after tGCI/R injury by activating ERK1/2 in H-NSCs to promote their proliferation and neurogenesis in the hippocampus. Therefore, LIG has potential for use in the prevention and/or treatment of POCD.

RTMS alleviates cognitive and neural oscillatory deficits induced by hindlimb unloading in mice via maintaining balance between glutamatergic and GABAergic systems

Microgravity, as a part of the stress of space flight, has several negative effects on cognitive functions. Repetitive transcranial magnetic stimulation (rTMS), as a novel non-invasive technique, could be an effective approach to alleviated cognitive decline, applied in both preclinical and clinical studies. Neural oscillations and their interactions are involved in cognitive functions and support the communication of neural information. The neural oscillation could be a window from which we may understand what happens in the brain. The current study aimed to explore if 15 Hz rTMS plays a neural modulation role in a mouse model of hindlimb unloading. We hypothezed that rTMS can improve the cognitive and neural oscillatory deficits induced by hindlimb unloading via maintaining the balance between glutamatergic and GABAergic systems. Our data show that rTMS can significantly alleviate behavior deficits, modulate theta oscillation, improve the disturbed power distribution of theta oscillation and the decreased strength of Cross-Frequency Coupling in the dentate gyrus region, and effectively mitigated the blocked communication of neural information in the perforant pathway (PP)―dentate gyrus (DG) neural pathway in Hu mice. Furthermore, biochemical analysis using high-performance liquid chromatography and Western blot assay confirmed that rTMS increases the low expression of glutamate (Glu) and N-Methyl d-Aspartate receptor subtype 2B (NR2B) and decreases the high expression of γ-aminobutyric acid (GABA), 67 KDa isoform of glutamate decarboxylase (GAD67), and GABA type A receptor subunit alpha1 (GABAARα1) in the hippocampus of Hu mice. Taken together, the results suggest that rTMS plays a significant neural modulation role in the hippocampal neural activity disorders induced by Hu, which possibly depends on rTMS maintaining the balance of glutamatergic and gamma-aminobutyric acidergic (GABAergic) systems.

Multimodal neural recordings with Neuro-FITM uncover diverse patterns of cortical-hippocampal interactions.

Many cognitive processes require communication between the neocortex and the hippocampus. However, coordination between large-scale cortical dynamics and hippocampal activity is not well understood, partially due to the difficulty in simultaneously recording from those regions. In the present study, we developed a flexible, insertable and transparent microelectrode array (Neuro-FITM) that enables investigation of cortical-hippocampal coordinations during hippocampal sharp-wave ripples (SWRs). Flexibility and transparency of Neuro-FITM allow simultaneous recordings of local field potentials and neural spiking from the hippocampus during wide-field calcium imaging. These experiments revealed that diverse cortical activity patterns accompanied SWRs and, in most cases, cortical activation preceded hippocampal SWRs. We demonstrated that, during SWRs, different hippocampal neural population activity was associated with distinct cortical activity patterns. These results suggest that hippocampus and large-scale cortical activity interact in a selective and diverse manner during SWRs underlying various cognitive functions. Our technology can be broadly applied to comprehensive investigations of interactions between the cortex and other subcortical structures.

Electromagnetic field protects against cognitive and synaptic plasticity impairment induced by electrical kindling in rats

Kindling results in abnormal synaptic potentiation and significant impairment in learning and memory. Electromagnetic field (EMF) effects on learning and memory in kindled animals and its effects on hippocampal neural activity are largely unknown. In the current study, the effects of EMF on learning and memory, as well as hippocampal synaptic plasticity, in kindled rats were investigated. EMF (10 mT; 100 Hz) was applied to fully kindled animals one hour/day for a period of one week. The behavioral and electrophysiological studies were performed 24 h following the EMF application. The kindled rats showed spatial learning deficits during the training phase of the Morris water maze (MWM) test. Moreover, there were increments in escape latency and path length compared to the sham group. The kindled rats spent less time in the target-quadrant probe test, indicating spatial memory impairment. Applying EMF to the KEMF group (kindling + EMF) restored learning and memory, and decreased escape latency and path length significantly compared to the kindled group. EMF alone had no significant effects on the learning and memory parameters. Based on the open field (OF) test results, EMF alone in the EMF group, but not in the kindled or the KEMF groups, decreased the total traveled distance and increased the spent time in the peripheral zone, compared to the sham group. Based on electrophysiological results, applying EMF in the KEMF group returned the ability of synaptic potentiation to the hippocampal CA1 area and high-frequency stimulation induced long-term potentiation (LTP). Accordingly, EMF can be considered a potential therapy for seizure-induced deficits in learning and memory.

Chronic social defeat stress impairs goal-directed behavior through dysregulation of ventral hippocampal activity in male mice

Chronic stress is a risk factor for a variety of psychiatric disorders, including depression. Although impairments to motivated behavior are a major symptom of clinical depression, little is known about the circuit mechanisms through which stress impairs motivation. Furthermore, research in animal models for depression has focused on impairments to hedonic aspects of motivation, whereas patient studies suggest that impairments to appetitive, goal-directed motivation contribute significantly to motivational impairments in depression. Here, we characterized goal-directed motivation in repeated social defeat stress (R-SDS), a well-established mouse model for depression in male mice. R-SDS impaired the ability to sustain and complete goal-directed behavior in a food-seeking operant lever-press task. Furthermore, stress-exposed mice segregated into susceptible and resilient subpopulations. Interestingly, susceptibility to stress-induced motivational impairments was unrelated to stress-induced social withdrawal, another prominent effect of R-SDS in mouse models. Based on evidence that ventral hippocampus (vHP) modulates sustainment of goal-directed behavior, we monitored vHP activity during the task using fiber photometry. Successful task completion was associated with suppression of ventral hippocampal neural activity. This suppression was diminished after R-SDS in stress-susceptible but not stress-resilient mice. The serotonin selective reuptake inhibitor (SSRI) escitalopram and ketamine both normalized vHP activity during the task and restored motivated behavior. Furthermore, optogenetic vHP inhibition was sufficient to restore motivated behavior after stress. These results identify vHP hyperactivity as a circuit mechanism of stress-induced impairments to goal-directed behavior and a putative biomarker that is sensitive to antidepressant treatments and that differentiates susceptible and resilient individuals.

Melamine disrupts spatial reversal learning and learning strategy via inhibiting hippocampal BDNF-mediated neural activity.

Although several studies showed adverse neurotoxic effects of melamine on hippocampus (HPC)-dependent learning and reversal learning, the evidence for this mechanism is still unknown. We recently demonstrated that intra-hippocampal melamine injection affected the induction of long-term depression, which is associated with novelty acquisition and memory consolidation. Here, we infused melamine into the HPC of rats, and employed behavioral tests, immunoblotting, immunocytochemistry and electrophysiological methods to sought evidence for its effects on cognitive flexibility. Rats with intra-hippocampal infusion of melamine displayed dose-dependent increase in trials to the criterion in reversal learning, with no locomotion or motivation defect. Compared with controls, melamine-treated rats avoided HPC-dependent place strategy. Meanwhile, the learning-induced BDNF level in the HPC neurons was significantly reduced. Importantly, bilateral intra-hippocampal BDNF infusion could effectively mitigate the suppressive effects of melamine on neural correlate with reversal performance, and rescue the strategy bias and reversal learning deficits. Our findings provide first evidence for the effect of melamine on cognitive flexibility and suggest that the reversal learning deficit is due to the inability to use place strategy. Furthermore, the suppressive effects of melamine on BDNF-mediated neural activity could be the mechanism, thus advancing the understanding of compulsive behavior in melamine-induced and other neuropsychiatric disorders.

The Role of Hippocampal-Ventromedial Prefrontal Cortex Neural Dynamics in Building Mental Representations.

The hippocampus and ventromedial prefrontal cortex (vmPFC) play key roles in numerous cognitive domains including mind-wandering, episodic memory, and imagining the future. Perspectives differ on precisely how they support these diverse functions, but there is general agreement that it involves constructing representations composed of numerous elements. Visual scenes have been deployed extensively in cognitive neuroscience because they are paradigmatic multielement stimuli. However, it remains unclear whether scenes, rather than other types of multifeature stimuli, preferentially engage hippocampus and vmPFC. Here, we leveraged the high temporal resolution of magnetoencephalography to test participants as they gradually built scene imagery from three successive auditorily presented object descriptions and an imagined 3-D space. This was contrasted with constructing mental images of nonscene arrays that were composed of three objects and an imagined 2-D space. The scene and array stimuli were, therefore, highly matched, and this paradigm permitted a closer examination of step-by-step mental construction than has been undertaken previously. We observed modulation of theta power in our two regions of interest-anterior hippocampus during the initial stage and vmPFC during the first two stages, of scene relative to array construction. Moreover, the scene-specific anterior hippocampal activity during the first construction stage was driven by the vmPFC, with mutual entrainment between the two brain regions thereafter. These findings suggest that hippocampal and vmPFC neural activity is especially tuned to scene representations during the earliest stage of their formation, with implications for theories of how these brain areas enable cognitive functions such as episodic memory.