Medial Hippocampus Research Articles

Neuroprotection mediated by prolactin against streptozotocin injury in brain rat areas

Prolactin has been recognized as neuroprotective hormone against various types of neuronal damage. This study was aimed to determine if prolactin protects against streptozotocin injury. A series of experiments were performed to determine neuronal survival by counting total neurons in medial hippocampus cortex and cerebellum. Astrogliosis was determined by immunofluorescence assays using GFAP, and behavioral improvement by prolactin after neuronal damage was determined by open-field and light–dark box tests. Results demonstrated that prolactin induced significant neuronal survival in both the hippocampus and cortex, but not in the cerebellum. No increase in astrogliosis was identified, but a significant reduction in anxiety levels was observed. Overall data indicate that prolactin may protect against a complex form of cell damage including oxidant stress and metabolic disruption by streptozotocin. Prolactin may be helpful strategy in the treatment of neuronal damage in neurological diseases.

Scene-selectivity in CA1/subicular complex: Multivoxel pattern analysis at 7T

Prior univariate functional magnetic resonance imaging (fMRI) studies in humans suggest that the anteromedial subicular complex of the hippocampus is a hub for scene-based cognition. However, it is possible that univariate approaches were not sufficiently sensitive to detect scene-related activity in other subfields that have been implicated in spatial processing (e.g., CA1). Further, as connectivity-based functional gradients in the hippocampus do not respect classical subfield boundary definitions, category selectivity may be distributed across anatomical subfields. Region-of-interest approaches, therefore, may limit our ability to observe category selectivity across discrete subfield boundaries. To address these issues, we applied searchlight multivariate pattern analysis to 7T fMRI data of healthy adults who undertook a simultaneous visual odd-one-out discrimination task for scene and non-scene (including face) visual stimuli, hypothesising that scene classification would be possible in multiple hippocampal regions within, but not constrained to, anteromedial subicular complex and CA1. Indeed, we found that the scene-selective searchlight map overlapped not only with anteromedial subicular complex (distal subiculum, pre/para subiculum), but also inferior CA1, alongside posteromedial (including retrosplenial) and parahippocampal cortices. Probabilistic overlap maps revealed gradients of scene category selectivity, with the strongest overlap located in the medial hippocampus, converging with searchlight findings. This was contrasted with gradients of face category selectivity, which had stronger overlap in more lateral hippocampus, supporting ideas of parallel processing streams for these two categories. Our work helps to map the scene, in contrast to, face processing networks within, and connected to, the human hippocampus.

The anterior medial hippocampus contributes to both recall and familiarity-based memory for scenes

The hippocampus is usually associated with recall memory, whereas its contribution to familiarity-based memory is debated. Growing evidence support the idea that this structure participates to any cognitive process performed on scene representations. In parallel, differences in functional specialisation and cortical connectivity were found across the longitudinal and transverse axes of the hippocampus. Here we reanalysed functional MRI data from 51 participants showing stronger engagement of the hippocampus in recall, familiarity-based recognition and rejection, and visual discrimination, of scenes compared to single objects. A conjunction analysis between these four tasks revealed a set of occipital, medial temporal, posterior cingulate, and parietal regions, matching the scene construction network described in the literature. Crucially, we found that the anterior medial part of the hippocampus was consistently involved in all tasks investigated for scene stimuli. These findings support that the hippocampus can contribute to both recall and familiarity-based memory, depending on stimulus type. More generally, this bolsters the recent proposal that circumscribed regions within the hippocampus may underpin specific cognitive mechanisms.

A Woman With Kelch-like Protein-11 Encephalitis and Unmasked Metastatic Carcinoma

Objective To illustrate a case of a woman with rhombencephalitis with antibodies to Kelch-like protein-11 (KLHL11) and a metastatic carcinoma. Background KLHL11 encephalitis is an autoimmune paraneoplastic syndrome first described in 2019. The clinical presentation consists of a brainstem cerebellar syndrome with symptoms of hearing loss, diplopia, vertigo and ataxia. This entity has been mostly described in male patients with associated testicular seminomas. Few cases have been described in women. This is a case of a woman with a history of hysterectomy and oophorectomy with KLHL11 encephalitis and an associated aortocaval tumor. Design/Methods NA. Results The patient was a 62-year-old woman that presented to clinic with a 9-month history of vertigo, progressive bilateral sensorineural hearing loss, diplopia, oscillopsia, ataxia and bilateral tremor. Her MRI brain obtained 8 months after symptom onset showed T2 hyperintense lesions in the inferior cerebellar hemispheres and right medial hippocampus with mild contrast enhancement in these areas. Cerebral spinal fluid analysis showed a lymphocytic pleocytosis, elevated protein, and negative infectious work-up. She completed 5 days of intravenous methylprednisolone and continued a steroid taper. She noted mild to moderate improvement in tremors, gait, and diplopia after steroids. Her symptoms, however worsened as she tapered her steroid dose. Serum KLHL11 antibody levels were positive at a titer of 1:7680. Computed tomography of the chest, abdomen and pelvis did not reveal any evidence of malignancy. However, whole body proton emission tomography/computed tomography (PET CT) revealed a large hypermetabolic aortocaval mass soft tissue mass. A biopsy of the mass showed pathology consistent with a metastatic carcinoma of gynecologic origin for which the patient is undergoing chemotherapy with plans for possible tumor debulking. Conclusions This case highlights the importance of considering KLHL-11 encephalitis in female patients presenting with rhombencephalitis, and the need for adequate malignancy evaluation in this disorder.

Prefrontal projections to the nucleus reuniens signal behavioral relevance of stimuli during associative learning

The nucleus reuniens (RE) is necessary for memories dependent on the interaction between the medial prefrontal cortex (mPFC) and hippocampus (HPC). One example is trace eyeblink conditioning, in which the mPFC exhibits differential activity to neutral conditioned stimuli (CS) depending on their contingency with an aversive unconditioned stimulus (US). To test if this relevancy signal is routed to the RE, we photometrically recorded mPFC axon terminals within the RE and tracked their changes with learning. As a comparison, we measured prefrontal terminal activity in the mediodorsal thalamus (MD), which lacks connectivity with the HPC. In naïve male rats, prefrontal terminals within the RE were not strongly activated by tone or light. As the rats associated one of the stimuli (CS+) with the US, terminals gradually increased their response to the CS+ but not the other stimulus (CS-). In contrast, stimulus-evoked responses of prefrontal terminals within the MD were strong even before conditioning. They also became augmented only to the CS+ in the first conditioning session; however, the degree of activity differentiation did not improve with learning. These findings suggest that associative learning selectively increased mPFC output to the RE, signaling the behavioral relevance of sensory stimuli.

Chronic Cognitive and Cerebrovascular Function after Mild Traumatic Brain Injury in Rats.

Severe traumatic brain injury (TBI) results in cognitive dysfunction in part due to vascular perturbations. In contrast, the long-term vasculo-cognitive pathophysiology of mild TBI (mTBI) remains unknown. We evaluated mTBI effects on chronic cognitive and cerebrovascular function and assessed their interrelationships. Sprague-Dawley rats received midline fluid percussion injury (n = 20) or sham (n = 21). Cognitive function was assessed (3- and 6-month novel object recognition [NOR], novel object location [NOL], and temporal order object recognition [TOR]). Six-month cerebral blood flow (CBF) and cerebral blood volume (CBV) using contrast magnetic resonance imaging (MRI) and ex vivo circle of Willis artery endothelial and smooth muscle-dependent function were measured. mTBI rats showed significantly impaired NOR, with similar trends (non-significant) in NOL/TOR. Regional CBF and CBV were similar in sham and mTBI. NOR correlated with CBF in lateral hippocampus, medial hippocampus, and primary somatosensory barrel cortex, whereas it inversely correlated with arterial smooth muscle-dependent dilation. Six-month baseline endothelial and smooth muscle-dependent arterial function were similar among mTBI and sham, but post-angiotensin 2 stimulation, mTBI showed no change in smooth muscle-dependent dilation from baseline response, unlike the reduction in sham. mTBI led to chronic cognitive dysfunction and altered angiotensin 2-stimulated smooth muscle-dependent vasoreactivity. The findings of persistent pathophysiological consequences of mTBI in this animal model add to the broader understanding of chronic pathophysiological sequelae in human mild TBI.

Imaging the influence of peripheral TRPV1-signaling on cerebral nociceptive processing applying fMRI-based graph theory in a resiniferatoxin rat model.

Resiniferatoxin (RTX), an extract from the spurge plant Euphorbia resinifera, is a potent agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1), mainly expressed on peripheral nociceptors—a prerequisite for nociceptive heat perception. Systemic overdosing of RTX can be used to desensitize specifically TRPV1-expressing neurons, and was therefore utilized here to selectively characterize the influence of TRPV1-signaling on central nervous system (CNS) temperature processing. Resting state and CNS temperature processing of male rats were assessed via functional magnetic resonance imaging before and after RTX injection. General linear model-based and graph-theoretical network analyses disentangled the underlying distinct CNS circuitries. At baseline, rats displayed an increase of nociception-related response amplitude and activated brain volume that correlated highly with increasing stimulation temperatures. In contrast, RTX-treated rats showed a clear disruption of thermal nociception, reflected in a missing increase of CNS responses to temperatures above 48°C. Graph-theoretical analyses revealed two distinct brain subnetworks affected by RTX: one subcortical (brainstem, lateral and medial thalamus, hippocampus, basal ganglia and amygdala), and one cortical (primary sensory, motor and association cortices). Resting state analysis revealed first, that peripheral desensitization of TRPV1-expressing neurons did not disrupt the basic resting-state-network of the brain. Second, only at baseline, but not after RTX, noxious stimulation modulated the RS-network in regions associated with memory formation (e.g. hippocampus). Altogether, the combination of whole-brain functional magnetic resonance imaging and RTX-mediated desensitization of TRPV1-signaling provided further detailed insight into cerebral processing of noxious temperatures.

The Medial Prefrontal Cortex, Nucleus Accumbens, Basolateral Amygdala, and Hippocampus Regulate the Amelioration of Environmental Enrichment and Cue in Fear Behavior in the Animal Model of PTSD.

A growing body of evidence showed that environmental enrichment (EE) ameliorated footshock-induced fear behavior of posttraumatic stress disorder (PTSD). However, no research comprehensively tested the effect of EE, cue, and the combination of EE and cue in footshock-induced fear behavior of PTSD symptoms. The present study addressed this issue and examined whether the medial prefrontal cortex (mPFC, including the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL)), the nucleus accumbens (NAc), the basolateral amygdala (BLA), and the hippocampus (e.g., CA1, CA3, and dentate gyrus (DG)) regulated the amelioration of the EE, cue, or the combination of EE and cue. The results showed that EE or cue could reduce fear behavior. The combination of EE and cue revealed a stronger decrease in fear behavior. The cue stimulus may play an occasion setting or a conditioned stimulus to modulate the reduction in fear behavior induced by footshock. Regarding the reduction of the EE in fear behavior, the Cg1 and IL of the mPFC and the NAc upregulated the c-Fos expression; however, the BLA downregulated the c-Fos expression. The mPFC (i.e., the Cg1, PrL, and IL) and the hippocampus (i.e., the CA1, CA3, and DG) downregulated the c-Fos expression in the suppression of the cue in fear behavior. The interaction of EE and cue in reduction of fear behavior occurred in the Cg1 and NAc for the c-Fos expression. The data of c-Fos mRNA were similar to the findings of the c-Fos protein expression. These findings related to the EE and cue modulations in fear behavior may develop a novel nonpharmacological treatment in PTSD.

P.0133 Age-related changes in neurotransmitter markers in the medial septum and hippocampus in rats: relationship with memory impairment

P.0133 Age-related changes in neurotransmitter markers in the medial septum and hippocampus in rats: relationship with memory impairment

Interneuron Heterotopia in the Lis1 Mutant Mouse Cortex Underlies a Structural and Functional Schizophrenia-Like Phenotype.

LIS1 is one of the principal genes related to Type I lissencephaly, a severe human brain malformation characterized by an abnormal neuronal migration in the cortex during embryonic development. This is clinically associated with epilepsy and cerebral palsy in severe cases, as well as a predisposition to developing mental disorders, in cases with a mild phenotype. Although genetic variations in the LIS1 gene have been associated with the development of schizophrenia, little is known about the underlying neurobiological mechanisms. We have studied how the Lis1 gene might cause deficits associated with the pathophysiology of schizophrenia using the Lis1/sLis1 murine model, which involves the deletion of the first coding exon of the Lis1 gene. Homozygous mice are not viable, but heterozygous animals present abnormal neuronal morphology, cortical dysplasia, and enhanced cortical excitability. We have observed reduced number of cells expressing GABA-synthesizing enzyme glutamic acid decarboxylase 67 (GAD67) in the hippocampus and the anterior cingulate area, as well as fewer parvalbumin-expressing cells in the anterior cingulate cortex in Lis1/sLis1 mutants compared to control mice. The cFOS protein expression (indicative of neuronal activity) in Lis1/sLis1 mice was higher in the medial prefrontal (mPFC), perirhinal (PERI), entorhinal (ENT), ectorhinal (ECT) cortices, and hippocampus compared to control mice. Our results suggest that deleting the first coding exon of the Lis1 gene might cause cortical anomalies associated with the pathophysiology of schizophrenia.

Abstract 2560: Plasticity-related signaling pathways in the medial prefrontal cortex and hippocampus as potential targets of the antidepressant vortioxetine in reversing cognitive impairments after androgen deprivation therapy for prostate cancer

Abstract Androgen deprivation therapy (ADT) is a frontline treatment for prostate cancer but induces profound cognitive impairment in more than half of patients. This significantly reduces quality of life for cancer survivors and their families. Deficits occur in cognitive domains associated with function of the hippocampus (Hipp) and medial prefrontal cortex (mPFC) and increase in severity with duration of treatment. Therefore, it may be possible to slow or reverse the impairment. In preclinical studies, we reported that vortioxetine, a novel multi-modal antidepressant that has been shown to improve cognitive impairment in depressed patients, may reverse the ADT-induced impairment. Our lab established a rodent model of ADT in which surgically castrated rats display deficits in cognitive flexibility and visuospatial recognition, measures of prefrontal executive function and hippocampal spatial learning, respectively. We also found that castration reduces response of the mPFC to activation of the afferent pathway from the vHipp in anesthetized animals. Chronic dietary vortioxetine (28mg/kg/day) normalized response in this pathway and reversed the cognitive impairments associated with both the mPFC and Hipp. In a microarray study (Agilent Technologies, Inc.) of tissue collected from the mPFC, dorsal-, and ventral-Hipp, we found that castration altered over 1,000 genes in each of these regions (adjusted p <0.05). Vortioxetine did not have a significant main effect on individual genes, but pathway analysis revealed significant changes in processes involved in synaptic plasticity, such as synapse formation, axonogenesis, and MAPK signaling. In the present study, qPCR and western blot analyses were used to investigate potential ADT- and vortioxetine-induced changes in candidate factors. Factors were identified in the top-hit pathways from the vortioxetine x castration microarray analysis and confirmed by qPCR. These included plasticity-related proteins such as Arc, Akt, CREB, mGlur1, and PSD95, among others. Changes in expression and phosphorylation were further determined using western blots. Early results indicate that vortioxetine selectively reversed the reduced expression induced by castration for some, but not all, of these proteins, including CREB and mGlur1 (p<0.05). Experiments are underway to identify potential alterations in protein phosphorylation, as changes in activation rather than expression may also be important to the beneficial effects of vortioxetine. These results suggest that vortioxetine may reverse deficits in executive function and visuospatial recognition after ADT by modulating structural and functional plasticity in mPFC and Hipp. Citation Format: Alexandra M. Vaiana, Roman Fernandez, Jonathan Gelfond, Teresa L. Johnson-Pais, Robin Leach, Chethan Ramamurthy, Ian Thompson, David A. Morilak. Plasticity-related signaling pathways in the medial prefrontal cortex and hippocampus as potential targets of the antidepressant vortioxetine in reversing cognitive impairments after androgen deprivation therapy for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2560.

Hippocampal shape across the healthy lifespan and its relationship with cognition

The study of the hippocampus across the healthy adult lifespan has rendered inconsistent findings. While volumetric measurements have often been a popular technique for analysis, more advanced morphometric techniques have demonstrated compelling results that highlight the importance and improved specificity of shape-based measures. Here, the MAGeT Brain algorithm was applied on 134 healthy individuals aged 18–81 years old to extract hippocampal subfield volumes and hippocampal shape measurements, namely: local surface area (SA) and displacement. We used linear-, second- or third-order natural splines to examine the relationships between hippocampal measures and age. In addition, partial least squares analyses were performed to relate volume and shape measurements with cognitive and demographic information. Volumetric results indicated a relative preservation of the right cornus ammonis 1 with age and a global volume reduction linked with older age, female sex, lower levels of education and cognitive performance. Vertex-wise analysis demonstrated an SA preservation in the anterior hippocampus with a peak during the sixth decade, while the posterior hippocampal SA gradually decreased across lifespan. Overall, SA decrease was linked to older age, female sex and, to a lesser extent lower levels of education and cognitive performance. Outward displacement in the lateral hippocampus and inward displacement in the medial hippocampus were enlarged with older age, lower levels of cognition and education, indicating an accentuation of the hippocampal “C” shape with age. Taken together, our findings suggest that vertex-wise analyses have higher spatial specifity and that sex, education, and cognition are implicated in the differential impact of age on hippocampal subregions throughout its anteroposterior and medial-lateral axes. This article is part of the Virtual Special Issue titled COGNITIVE NEU- ROSCIENCE OF HEALTHY AND PATHOLOGICAL AGING. The full issue can be found on ScienceDirect at https://www.sciencedirect.com/journal/neurobiology-of-aging/special-issue/105379XPWJP.

Clinicoradiological features in amyotrophic lateral sclerosis patients with olfactory dysfunction

Objective: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by motor neuron involvement. Although olfactory dysfunction has been described in ALS, clinicoradiological features associated with the olfactory dysfunction remain poorly understood. Methods: We enrolled 30 patients with ALS and age- and sex-matched 53 healthy controls (HCs). All participants underwent the odor stick identification test for Japanese (OSIT-J) and clinical assessments, including disease duration, ALSFRS-R, site of onset, forced vital capacity, and cognitive examinations that reflected the general, executive, memory and language function. We investigated the associations between OSIT-J score and clinical features and examined atrophic changes by voxel-based morphometry (VBM) analysis to MRI. Results: The OSIT-J score was significantly lower in ALS patients than HCs (6.9 ± 3.2 vs. 9.8 ± 1.9, p < 0.001). In ALS, there were significant relationships between OSIT-J score and age at examination, frontal assessment battery, word fluencies, digit span forward, and ADAS-Jcog recognition, but not education, disease type, duration, ALSFRS-R and, %VC. Multiple regression analysis with stepwise method showed the only ADAS-Jcog recognition substantially predicted OSIT-J score. VBM analysis with age, sex, total intracranial volume, and ADAS-Jcog recognition as covariates showed OSIT-J scores were substantially correlated with atrophic changes of left orbital cortex consisting of gyrus rectus and medial orbital gyrus and right hippocampus in ALS. Conclusion: ALS patients could show substantial olfactory dysfunction in association with orbital cortex and hippocampus involvements. The olfactory examination could be a useful marker for screening of frontotemporal alteration in ALS.

Electronegative very-low-density lipoprotein induces brain inflammation and cognitive dysfunction in mice

Epidemiologic studies have indicated that dyslipidemia may facilitate the progression of cognitive dysfunction. We previously showed that patients with metabolic syndrome (MetS) had significantly higher plasma levels of electronegative very-low-density lipoprotein (VLDL) than did healthy controls. However, the effects of electronegative-VLDL on the brain and cognitive function remain unclear. In this study, VLDL isolated from healthy volunteers (nVLDL) or patients with MetS (metVLDL) was administered to mice by means of tail vein injection. Cognitive function was assessed by using the Y maze test, and plasma and brain tissues were analyzed. We found that mice injected with metVLDL but not nVLDL exhibited significant hippocampus CA3 neuronal cell loss and cognitive dysfunction. In mice injected with nVLDL, we observed mild glial cell activation in the medial prefrontal cortex (mPFC) and hippocampus CA3. However, in mice injected with metVLDL, plasma and brain TNF-α and Aβ-42 levels and glial cell activation in the mPFC and whole hippocampus were higher than those in control mice. In conclusion, long-term exposure to metVLDL induced levels of TNF-α, Aβ-42, and glial cells in the brain, contributing to the progression of cognitive dysfunction. Our findings suggest that electronegative-VLDL levels may represent a new therapeutic target for cognitive dysfunction.

Hippocampus anatomical structure and distribution of agrin proteoglycan and ryanodine receptor expression boost bird food caching behavior

Feeding habitats and behavior are connected with various environmental conditions and anatomical structures of the hippocampus, altogether with proteins expression level that may enhance their cognitive memory abilities. The current study investigated the cytoarchitecture anatomical variations, the differences in the hippocampus volume, and the distribution of the proteoglycan agrin and ryanodine receptor protein expression; in the brain hippocampus complex of three avian species (the hooded crow (Corvus cornix, food caching), the cattle egret (Bubulcus ibis, non-food caching), and the rock dove pigeon (Columba livia, food caching). The histological results demonstrated that the anatomical brain structure and cytoarchitecture did not reveal specific characterizing features expect for the hooded crow with large-sized soma. Immunohistochemical staining of hippocampus complex for agrin proteoglycans and ryanodine receptor calcium channels proteins showed a significant increase among the hippocampus of Corvus cornix brain in the medial hippocampus (HCm) and lateral hippocampus (HCl) with value P < 0.001, respectively. The highly expressed agrin may play a major role in constructing the neuronal plasticity and activity of neurons. Moreover, there were significant difference in the concerning hippocampus volume but neurons count did not appeared with for the storing and non-storing behavior. Therefore, the present study revealed a significant difference between storing and non-storing species in the expression of proteoglycan and ryanodine receptor calcium channels proteins. Comprehensively, the hippocampal complex cytoarchitecture altogether with proteoglycan and ryanodine receptor calcium channel proteins are important to birds for fulfilling their cognitive needs such as food caching.

Reduced structural covariance connectivity of defaut mode network and salience network in MRI-normal focal epilepsy.

Neuroimaging studies have found altered functional connectivity of default mode network (DMN) and salience network (SN) in patients with focal epilepsy (FE). However, the structural basis underlying the functional connectivity disturbance in the patients is still unclear. Sixteen MRI-normal FE and 22 healthy controls were included in the current study. The T1 structural image of each participant was obtained. Seed-based structural covariance connectivity was employed to investigate changes of structural covariance connectivity of DMN and SN in FE patients. We further evaluated gray matter volume changes of brain areas showing altered structural connectivity in the patients. We found that patients with FE showed reduced connectivity of posterior cingulate cortex and left medial prefrontal cortex, hippocampus and orbitofrontal cortex, and reduced connectivity of right fronto-insula cortex with left insula, orbitofrontal cortex, opercum part of inferior frontal cortex and right medial prefrontal cortex compared with healthy controls. Moreover, those brain areas showing significant reduced structural covariance connectivity in patients with FE also had a loss of gray matter volume, indicating that reduced structural connectivity of DMN and SN might be associated with gray matter atrophy in the patients. Those results highlight the crucial role of DMN and SN in the pathology of patients with FE, and provided structural basis for the functional disturbance of the two networks in this disease.

Effect of locomotion on the auditory steady state response of head-fixed mice

Objectives Electroencephalographic (EEG) examinations of the auditory steady-state response (ASSR) can non-invasively probe cortical function to generate the gamma-band (40 Hz) oscillation, which is increasingly applied to the neurophysiological studies on the rodent models of psychiatric disorders. Though, it has been well established that the brain activities are significantly modulated by the behavioural state (such as locomotion), how the ASSR is affected remains unclear. Methods We investigated the effect of locomotion by recording local field potential (LFP) evoked by 40-Hz click-train from multiple brain areas: auditory cortex (AC), medial geniculate body (MGB), hippocampus (HP) and prefrontal cortex (PFC), in head-fixed mice free to run on a treadmill. Comparisons were conducted on the LFPs during spontaneous movement and stationary conditions. Results We found that in both the auditory (AC and MGB) and non-auditory areas (HP and PFC), locomotion reduced the initial negative deflection of LFP (early response during 0–100 ms from stimulus onset), and had no significant effect on the ASSR phase-locking to the late stimulus (100–500 ms). Conclusions Our results suggest that different neural mechanisms contribute to the early response and ASSR, and the ASSR is a more robust biomarker to investigate the pathogenesis of neuropsychiatric disorders.

The Retrotransposition of L1 is Involved in the Reconsolidation of Contextual Fear Memory in Mice.

The long interspersed element-1 (L1) participates in memory formation, and DNA methylation patterns of L1 may suggest resilience or vulnerability factors for Post-Traumatic Stress Disorder (PTSD), of which the principal manifestation is a pathological exacerbation of fear memory. However, the unique roles of L1 in the reconsolidation of fear memory remain poorly understood. The study aimed to investigate the role of L1 in the reconsolidation of context-dependent fear memory. Mice underwent fear conditioning and fear recall in the observation chambers. Fear memory was assessed by calculating the percentage of time spent freezing in 5 min. The medial prefrontal cortex (mPFC) and hippocampus were removed for further analysis. Open Reading Frame 1 (ORF1) mRNA and ORF2 mRNA of L1 were analyzed by real-time quantitative polymerase chain reaction. After reactivation of fear memory, lamivudine was administered and its effects on fear memory reconsolidation were observed. ORF1 and ORF2 mRNA expressions in the mPFC and hippocampus after recent (24 h) and remote (14 days) fear memory recall exhibited augmentation via different temporal and spatial patterns. Reconsolidation of fear memory was markedly inhibited in mice treated with lamivudine, which could block L1. DNA methyltransferase mRNA expression declined following lamivudine treatment in remote fear memory recall. The retrotransposition of L1 participated in the reconsolidation of fear memory after reactivation of fear memory, and with lamivudine treatment, spontaneous recovery decreased with time after recent and remote fear memory recall, providing clues for understanding the roles of L1 in fear memory.

1994-P: Task-Oriented Connectivity Analysis of Disease-Dependent Effects of Diet

Previous results have demonstrated that short-term dieting attenuates neuronal inhibitory control on appetite measured with blood-oxygen-level-dependent (BOLD) responses to a food cue task. Because recent studies have suggested that functional connectivity measured during the task is strongly predictive of disease states, we sought to investigate the effect of weight loss on brain functional connectivity during the picture viewing task. Sixteen healthy obese (10F/6M, age 44.4±8 years, BMI 32.7±2) and 9 type 2 diabetes (T2DM) obese subjects (5F/4M, age 48±9, BMI 33.9±2) underwent functional MRI (fMRI) before and after an 8-week low-calorie diet. Brain connectivity (BOLD) was recorded while subjects viewed preselected images (high-calorie food, low-calorie food, and non-food). Participants lost 2.9±2.8 kg (p&amp;lt;0.05) weight after the diet. Using intrinsic connectivity distribution (ICD) analysis, there was a significant diet effect (p&amp;lt; 0.01) in the inferior pons, hypothalamus, and inferior medial hippocampus across all subjects. Diet by group interaction in ICD (p &amp;lt;0.001) was observed in the inferior anterior amygdala, inferior medial hippocampus, and hypothalamus, brain regions involved in the modulation of emotion and glucose metabolism. These results highlight the adaptive nature of neuronal control on diet and provide novel evidence for a variable nature of inhibitory neuronal adaptions in metabolic diseases. Disclosure C. Watt: None. T.K. Stanley: None. C. Lacadie: None. K.W.Y. Lam: None. M. Savoye: None. R. Sinha: None. T. Constable: None. D. Seo: None. J.J. Hwang: Research Support; Self; General Electric. R. Belfort-DeAguiar: Research Support; Self; Silver Palate Kitches. Funding National Institute of Diabetes and Digestive and Kidney Diseases (P30DK045735, K23 DK098286-02, R01DK020495); National Institutes of Health (UL1TR001863)

Brain microglial activation in chronic pain-associated affective disorder

A growing body of evidence from both clinical and animal studies indicates that chronic neuropathic pain is associated with comorbid affective disorders. Spinal cord microglial activation is involved in nerve injury-induced pain hypersensitivity characterizing neuropathic pain. However, there is a lack of thorough assessments of microglial activation in the brain after nerve injury. In the present study, we characterized microglial activation in brain sub-regions of CX3CR1GFP/+ mice after chronic constriction injury (CCI) of the sciatic nerve, including observations at delayed time points when affective brain dysfunctions such as depressive-like behaviors typically develop. Mice manifested chronic mechanical hypersensitivity immediately after CCI and developed depressive-like behaviors 8 weeks post-injury. Concurrently, significant increases of soma size and microglial cell number were observed in the medial prefrontal cortex (mPFC), hippocampus, and amygdala 8 weeks post-injury. Transcripts of CD11b, and TNF-α, genes associated with microglial activation or depressive-like behaviors, are correspondingly upregulated in these brain areas. Our results demonstrate that microglia are activated in specific brain sub-regions after CCI at delayed time points and imply that brain microglial activation plays a role in chronic pain-associated affective disorders.