Medial Nucleus Research Articles

Social isolation postweaning alters reward-related dopamine dynamics in a region-specific manner in adolescent male rats

Early development is characterized by dynamic transitions in brain maturation, which may be impacted by environmental factors. Here, we sought to determine the effects of social isolation from postweaning and during adolescence on reward behavior and dopaminergic signaling in male rats. Subjects were socially isolated or group housed at postnatal day 21. Three weeks later, extracellular dopamine concentrations were examined in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (NAc) during a feeding bout. Surprisingly, opposing effects were found in which increased mPFC dopamine concentrations were observed in group housed, but not isolated, rats. In stark contrast, increased dopamine levels were found in the NAc of isolated, but not group housed, rats. Moreover, the absence of an effect in the mPFC of the isolated rats could not be reversed by subsequent group housing, demonstrating the remarkable long-term effects on dopamine signaling dynamics. When provided a highly palatable food, the isolated subjects exhibited a dramatic increase in mPFC dopamine levels when the chocolate was novel, but no effects following chronic chocolate consumption. In contrast, the group housed subjects showed significantly increased dopamine levels only with chronic chocolate consumption. The dopamine changes were correlated with differences in behavioral measures. Importantly, the deficit in reward-related behavior during isolation could be reversed by microinjection of either dopamine or cocaine into the mPFC. Together, these data provide evidence that social isolation from postweaning and during adolescence alters reward-induced dopamine levels in a brain region-specific manner, which has important functional implications for reward-related behavior.

Altered functional connectivity of brainstem nuclei in new daily persistent headache: Evidence from resting-state functional magnetic resonance imaging.

The new daily persistent headache (NDPH) is a rare primary headache disorder. However, the underlying mechanisms of NDPH remain incompletely understood. This study aims to apply seed-based analysis to explore the functional connectivity (FC) of brainstem nuclei in patients with NDPH using resting-state functional magnetic resonance imaging (MRI). The FC analysis from the region of interest (ROI) to whole brain voxels was used to investigate 29 patients with NDPH and 37 well-matched healthy controls (HCs) with 3.0 Tesla MRI. The 76 nuclei in the brainstem atlas were defined as ROIs. Furthermore, we explored the correlations between FC and patients' clinical characteristics and neuropsychological evaluations. Patients with NDPH exhibited reduced FC in multiple brainstem nuclei compared to HCs (including right inferior medullary reticular formation, right mesencephalic reticular formation, bilateral locus coeruleus, bilateral laterodorsal tegmental nucleus-central gray of the rhombencephalon, median raphe, left medial parabrachial nucleus, periaqueductal gray, and bilateral ventral tegmental area-parabrachial pigmented nucleus complex) and increased FC in periaqueductal gray. No significant correlations were found between the FC of these brain regions and clinical characteristics or neuropsychological evaluations after Bonferroni correction (p > 0.00016). Our results demonstrated that patients with NDPH have abnormal FC of brainstem nuclei involved in the perception and regulation of pain and emotions.

The regulation of social factors on anxiety and microglial activity in nucleus accumbens of adolescent male mice: Influence of social interaction strategy

BackgroundAdolescence is a period characterized by a high vulnerability to emotional disorders, which are modulated by biological, psychological, and social factors. However, the underlying mechanisms remain poorly understood. MethodsCombining physical or emotional social defeat stress (PS and ES) and pair or isolation rearing conditions, we investigated the effects of stress type and social support on emotional behavior and central immune molecules in adolescent mice, including anxiety, social fear, and social interaction strategies, as well as changes in microglia-specific molecules (ionized calcium-binding adaptor molecule 1 (Iba1) and a cluster of differentiation molecule 11b (CD11b)) in the medial prefrontal cortex (mPFC), hippocampus (HIP), amygdala (AMY), and nucleus accumbens (NAc). ResultsMice exposed to both physical stress and isolated rearing condition exhibited the highest levels of anxiety, social fear, and microglial CD11b expression in the NAc. In terms of social support, pair-housing with siblings ameliorated social fear and NAc molecular changes in ES mice, but not in PS mice. The reason for the differential benefit from social support was attributed to the fact that ES mice exhibited more active and less passive social strategies in social environment compared to PS mice. Further, the levels of stress-induced social fear were positively associated with the expression of microglial CD11b in the NAc. ConclusionThese findings offer extensive evidence regarding the intricate effects of multiple social factors on social anxiety and immune alteration in the NAc of adolescent mice. Additionally, they suggest potential behavioral and immune intervention strategies for anxiety-related disorders in adolescents.

A novel GABAergic population in the medial vestibular nucleus maintains wakefulness and gates rapid eye movement sleep

Body rocking can either induce sleep or arousal. That is, the vestibular sense influences sleep-wake states. Neuronal interactions between sleep-wake systems and vestibular systems, however, remain unclear. In this study, we found that GABAergic neurons in the lateral part of the medial vestibular nucleus (LMVN), a primary vestibular afferent projection site, control sleep-wake states. Specific inhibition of LMVN GABAergic neurons revealed that the firing of LMVN GABAergic neurons underlies stable wakefulness and smooth transitions from non-rapid-eye-movement (NREM) sleep to rapid eye movement (REM) sleep and that LMVN GABAergic neurons do not affect body balance control in freely moving conditions. Selective axonal tracing of LMVN GABAergic neurons indicated that LMVN GABAergic neurons send axons not only to areas involved in vestibular and oculomotor functions but also to areas regulating sleep-wake states. Our findings suggest that LMVN GABAergic neurons stabilize wakefulness and gate the entry into REM sleep through the use of vestibular information.

Brief exposure to enriched environment rapidly shapes the glutamate synapses in the rat brain: A metaplastic fingerprint.

Environmental enrichment (EE) has been shown to produce beneficial effects in addiction disorders; however, due to its configurational complexity, the underlying mechanisms are not yet fully elucidated. Recent evidence suggests that EE, acting as a metaplastic agent, may affect glutamatergic mechanisms underlying appetitive memory and, in turn, modulate reward-seeking behaviours: here, we have investigated such a possibility following a brief EE exposure. Adult male Sprague-Dawley rats were exposed to EE for 22 h and the expression of critical elements of the glutamate synapse was measured 2h after the end of EE in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and hippocampus (Hipp) brain areas, which are critical for reward and memory. We focused our investigation on the expression of NMDA and AMPA receptor subunits, their scaffolding proteins SAP102 and SAP97, vesicular and membrane glutamate transporters vGluT1 and GLT-1, and critical structural components such as proteins involved in morphology and function of glutamatergic synapses, PSD95 and Arc/Arg3.1. Our findings demonstrate that a brief EE exposure induces metaplastic changes in glutamatergic mPFC, NAc and Hipp. Such changes are area-specific and involve postsynaptic NMDA/AMPA receptor subunit composition, as well as changes in the expression of their main scaffolding proteins, thus influencing the retention of such receptors at synaptic sites. Our data indicate that brief EE exposure is sufficient to dynamically modulate the glutamatergic synapses in mPFC-NAc-Hipp circuits, which may modulate rewarding and memory processes.

Dementia risk and thalamic nuclei volumetry in healthy midlife adults: the PREVENT Dementia study.

A reduction in the volume of the thalamus and its nuclei has been reported in Alzheimer's disease, mild cognitive impairment and asymptomatic individuals with risk factors for early-onset Alzheimer's disease. Some studies have reported thalamic atrophy to occur prior to hippocampal atrophy, suggesting thalamic pathology may be an early sign of cognitive decline. We aimed to investigate volumetric differences in thalamic nuclei in middle-aged, cognitively unimpaired people with respect to dementia family history and apolipoprotein ε4 allele carriership and the relationship with cognition. Seven hundred participants aged 40-59 years were recruited into the PREVENT Dementia study. Individuals were stratified according to dementia risk (approximately half with and without parental dementia history). The subnuclei of the thalamus of 645 participants were segmented on T1-weighted 3 T MRI scans using FreeSurfer 7.1.0. Thalamic nuclei were grouped into six regions: (i) anterior, (ii) lateral, (iii) ventral, (iv) intralaminar, (v) medial and (vi) posterior. Cognitive performance was evaluated using the computerized assessment of the information-processing battery. Robust linear regression was used to analyse differences in thalamic nuclei volumes and their association with cognitive performance, with age, sex, total intracranial volume and years of education as covariates and false discovery rate correction for multiple comparisons. We did not find significant volumetric differences in the thalamus or its subregions, which survived false discovery rate correction, with respect to first-degree family history of dementia or apolipoprotein ε4 allele status. Greater age was associated with smaller volumes of thalamic subregions, except for the medial thalamus, but only in those without a dementia family history. A larger volume of the mediodorsal medial nucleus (Pfalse discovery rate = 0.019) was associated with a faster processing speed in those without a dementia family history. Larger volumes of the thalamus (P = 0.016) and posterior thalamus (Pfalse discovery rate = 0.022) were associated with significantly worse performance in the immediate recall test in apolipoprotein ε4 allele carriers. We did not find significant volumetric differences in thalamic subregions in relation to dementia risk but did identify an interaction between dementia family history and age. Larger medial thalamic nuclei may exert a protective effect on cognitive performance in individuals without a dementia family history but have little effect on those with a dementia family history. Larger volumes of posterior thalamic nuclei were associated with worse recall in apolipoprotein ε4 carriers. Our results could represent initial dysregulation in the disease process; further study is needed with functional imaging and longitudinal analysis.

Activating Lobule VI PCTH+-Med Pathway in Cerebellum Blocks the Acquisition of Methamphetamine Conditioned Place Preference in Mice.

Cerebellum has been implicated in drug addiction; however, its underlying cellular populations and neuronal circuitry remain largely unknown. In the current study, we identified a neural pathway from tyrosine hydroxylase (TH)-positive Purkinje cells (PCTH+) in cerebellar lobule VI to calcium/calmodulin-dependent protein kinase II (CaMKII)-positive glutamatergic neurons in the medial cerebellar nucleus (MedCaMKII), forming the lobule VI PCTH+-MedCaMKII pathway in male mice. In naive male mice, inhibition of PCTH+ neurons activated Med neurons. During conditioned place preference (CPP) training, exposure to methamphetamine (METH) inhibited lobule VI PCTH+ neurons while excited MedCaMKII neurons in mice. Silencing MedCaMKII using a tetanus toxin light chain (tettox) suppressed the acquisition of METH CPP in mice but resulted in motor coordination deficits in naive mice. In contrast, activating lobule VI PCTH+ terminals within Med inhibited the activity of Med neurons and subsequently blocked the acquisition of METH CPP in mice without affecting motor coordination, locomotor activity, and sucrose reinforcements in naive mice. Our findings identified a novel lobule VI PCTH+-MedCaMKII pathway within the cerebellum and explored its role in mediating the acquisition of METH-preferred behaviors.

Effects of physical training on hypothalamic neuronal activation and expressions of vasopressin and oxytocin in SHR after running until fatigue.

To assess the influence of physical training on neuronal activation and hypothalamic expression of vasopressin and oxytocin in spontaneously hypertensive rats (SHR), untrained and trained normotensive rats and SHR were submitted to running until fatigue while internal body and tail temperatures were recorded. Hypothalamic c-Fos expression was evaluated in thermoregulatory centers such as the median preoptic nucleus (MnPO), medial preoptic nucleus (mPOA), paraventricular nucleus of the hypothalamus (PVN), and supraoptic nucleus (SON). The PVN and the SON were also investigated for vasopressin and oxytocin expressions. Although exercise training improved the workload performed by the animals, it was reduced in SHR and followed by increased internal body temperature due to tail vasodilation deficit. Physical training enhanced c-Fos expression in the MnPO, mPOA, and PVN of both strains, and these responses were attenuated in SHR. Vasopressin immunoreactivity in the PVN was also increased by physical training to a lesser extent in SHR. The already-reduced oxytocin expression in the PVN of SHR was increased in response to physical training. Within the SON, neuronal activation and the expressions of vasopressin and oxytocin were reduced by hypertension and unaffected by physical training. The data indicate that physical training counterbalances in part the negative effect of hypertension on hypothalamic neuronal activation elicited by exercise, as well as on the expression of vasopressin and oxytocin. These hypertension features seem to negatively influence the workload performed by SHR due to the hyperthermia derived from the inability of physical training to improve heat dissipation through skin vasodilation.

Inactivation of phosphodiesterase-4B gene in rat nucleus accumbens shell by CRISPR/Cas9 or positive allosteric modulation of the protein affects the motivation to chronically self-administer nicotine

Large scale human genome wide association studies (GWAS) have identified a growing pool of genes associated with cigarette smoking. One of the most prominent, phosphodiesterase-4B (PDE4B), has been associated with multiple smoking phenotypes. Although PDE4B modulates the half-life of neuronal cAMP, its precise role in smoking behaviors is unknown. To address this knowledge gap, we used a reverse translational approach. We inactivated PDE4B in bilateral medial nucleus accumbens shell (NAcs) neurons by injecting AAV containing a specific gRNA in female transgenic Cas9+ Long Evans rats. These rats then were given 23-h chronic access to nicotine intravenous self-administration (IVSA) under a schedule of increasing fixed ratios (FR). With the increased effort required at FR7, nicotine SA (i.e. active presses and drug infusions) declined significantly in controls, whereas it was maintained in the mutagenized group. A progressive ratio (PR) study also showed significantly greater cumulative nicotine infusions in the PDE4B-edited group. Hence, we hypothesized that enhanced PDE4B protein activity would reduce nicotine IVSA. A positive allosteric modulator, 2-(3-(4-chloro-3-fluorophenyl)-5-ethyl-1H-1,2,4-triazol-1-yl)-N-(3,5-dichlorobenzyl)acetamide (MR-L2), was microinfused into NAcs bilaterally at FR3 or FR5; in both cohorts, MR-L2 acutely reduced nicotine IVSA. In summary, these studies show that the activity of PDE4B regulates the capacity of NAcs to maintain nicotine IVSA in face of the cost of increasing work. This finding and the results of the PR study indicate that PDE4B affects the motivation to obtain nicotine. These reverse translational studies in rats provide insight into the motivational effects of NAcs PDE4B that advance our understanding of the smoking behaviors mapped in human GWAS.

Behavioral and Molecular Characterization of Prenatal Stress Effects on the C57BL/6J Genetic Background for the Study of Autism Spectrum Disorder.

Stress-inducing events during pregnancy are associated with aberrant neurodevelopment resulting in adverse psychiatric outcomes, including autism spectrum disorder (ASD). While numerous preclinical models for the study of ASD are frequently generated using C57BL/6J mice, few studies have investigated the effects of prenatal stress on this genetic background. In the current manuscript, we stressed C57BL/6 dams during gestation and examined numerous behavioral and molecular endophenotypes in the adult male and female offspring to characterize the resultant phenotype as compared with offspring born from nonstressed (NS) dams. Adult mice born from prenatal restraint stressed (PRS) dams demonstrated reduced sociability and reciprocal social interaction along with increased marble burying behaviors relative to mice born from nonstressed control dams. Differential expression of genes related to excitatory and inhibitory neurotransmission was evaluated in the medial prefrontal cortex, amygdala, hippocampus, nucleus accumbens and caudate putamen via qRT-PCR. The male PRS mouse behavioral phenotype coincided with aberrant expression of glutamate and GABA marker genes (e.g., Grin1, Grin2b, Gls, Gat1, Reln) in neural substrates of social behavior. Rescue of the male PRS sociability deficit by a known antipsychotic with epigenetic properties (i.e., clozapine (5 mg/kg) + 18 hr washout) indicated possible epigenetic regulation of genes that govern sociability. Clozapine treatment increased the expression levels of genes involved in DNA methylation, histone methylation, and histone acetylation in the nucleus accumbens. Identification of etiology-specific mechanisms underlying clinically relevant behavioral phenotypes may ultimately provide novel therapeutic interventions for the treatment of psychiatric disorders including ASD.

Atrophy patterns in hippocampus and amygdala subregions of depressed patients with Parkinson's disease

We aimed to explore the subregional atrophy patterns of the amygdala and hippocampus in Parkinson's disease (PD) with depression and their correlation with the severity of the depressive symptom. MRI scans were obtained for 34 depressed PD patients (DPD), 22 nondepressed PD patients (NDPD), and 28 healthy controls (HC). Amygdala and hippocampal subregions were automatically segmented, and the intergroup volume difference was compared. The relationships between the volumes of the subregions and depression severity were investigated. Logistic analysis and Receiver operator characteristic curve were used to find independent predictors of DPD. Compared with the HC group, atrophy of the bilateral lateral nucleus, left accessory basal nucleus, right cortical nucleus, right central nucleus, and right medial nucleus subregions of the amygdala were visible in the DPD group, while the right lateral nucleus subregion of the amygdala was smaller in the DPD group than in the NDPD group. The DPD group showed significant atrophy in the left molecular layer, left GC-DG, left CA3, and left CA4 subregions compared with the HC group for hippocampal subregion volumes. Also, the right lateral nuclei volume and disease duration were independent predictors of DPD. To sum up, DPD patients showed atrophy in multiple amygdala subregions and left asymmetric hippocampal subregions. The decreased amygdala and hippocampal subregion volumes were correlated with the severity of depressive symptoms. The volume of right lateral nuclei and disease duration could be used as a biomarker to detect DPD.

Neural connections of the torus semicircularis in the adult Zebrafish.

The torus semicircularis (TS) of teleosts is a key midbrain center of the lateral line and acoustic sensory systems. To characterize the TS in adult zebrafish, we studied their connections using the carbocyanine tracers applied to the TS and to other related nuclei and tracts. Two main TS nuclei, central and ventrolateral, were differentiable by their afferent connections. From central TS, (TSc) numerous toropetal cells were labeled bilaterally in several primary octaval nuclei (anterior, magnocellular, descending, and posterior octaval nuclei), in the secondary octaval nucleus, in the caudal octavolateralis nucleus, and in the perilemniscular region. In the midbrain, numerous toropetal cells were labeled in the contralateral TSc. In the diencephalon, toropetal cells labeled from the TSc were observed ipsilaterally in the medial prethalamic nucleus and the periventricular posterior tubercle nucleus. TSc toropetal neurons were also labeled bilaterally in the hypothalamic anterior tuberal nucleus (ATN) and ipsilaterally in the parvicellular preoptic nucleus but not in the telencephalon. Tracer application to the medial octavolateralis nucleus revealed contralateral projections to the ventrolateral TS (TSvl), whereas tracer application to the secondary octaval nucleus labeled fibers bilaterally in TSc and neurons in rostral TSc. The TSc sends ascending fibers to the ipsilateral lateral preglomerular region that, in turn, projects to the pallium. Application of DiI to the optic tectum labeled cells and fibers in the TSvl, whereas application of DiI to the ATN labeled cells and fibers in the TSc. These results reveal that the TSvl and TSc are mainly related with the mechanosensory lateral line and acoustic centers, respectively, and that they show different higher order connections.

Abuse-like toluene exposure during early adolescence alters subsequent ethanol and cocaine behavioral effects and brain monoamines in male mice

Currently, there is a gap in understanding the neurobiological impact early adolescent toluene exposure has on subsequent actions of other drugs. Adolescent (PND 28–32) male Swiss-Webster mice (N = 210) were exposed to 0, 2000, or 4000 ppm of toluene vapor for 30 min/day for 5 days. Immediately following the last toluene exposure (PND 32; n = 15) or after a short delay (PND 35; n = 15), a subset of subjects' brains was collected for monoamine analysis. Remaining mice were assigned to one of two abstinence periods: a short 4-day (PND 36) or long 12-day (PND 44) delay after toluene exposure. Mice were then subjected to a cumulative dose response assessment of either cocaine (0, 2.5, 5, 10, 20 mg/kg; n = 60), ethanol (0, 0.5, 1, 2, 4 g/kg; n = 60), or saline (5 control injections; n = 60). Toluene concentration-dependently increased locomotor activity during exposure. When later challenged, mice exposed previously to toluene were significantly less active after cocaine (10 and 20 mg/kg) compared to air-exposed controls. Animals were also less active at the highest dose of alcohol (4 g/kg) following prior exposure to 4000 ppm when compared to air-exposed controls. Analysis of monoamines and their metabolites using High Pressure Liquid Chromatography (HPLC) within the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), dorsal striatum (dSTR), and ventral tegmental area (VTA) revealed subtle effects on monoamine or metabolite levels following cumulative dosing that varied by drug (cocaine and ethanol) and abstinence duration. Our results suggest that early adolescent toluene exposure produces behavioral desensitization to subsequent cocaine-induced locomotor activity with subtle enhancement of ethanol's depressive effects and less clear impacts on levels of monoamines.

Impaired effective functional connectivity in the social preference of children with autism spectrum disorder.

The medial prefrontal cortex (mPFC), amygdala (Amyg), and nucleus accumbens (NAc) have been identified as critical players in the social preference of individuals with ASD. However, the specific pathophysiological mechanisms underlying this role requires further clarification. In the current study, we applied Granger Causality Analysis (GCA) to investigate the neural connectivity of these three brain regions of interest (ROIs) in patients with ASD, aiming to elucidate their associations with clinical features of the disorder. Resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired from the ABIDE II database, which included 37 patients with ASD and 50 typically developing (TD) controls. The mPFC, Amyg, and NAc were defined as ROIs, and the differences in fractional amplitude of low-frequency fluctuations (fALFF) within the ROIs between the ASD and TD groups were computed. Subsequently, we employed GCA to investigate the bidirectional effective connectivity between the ROIs and the rest of the brain. Finally, we explored whether this effective connectivity was associated with the social responsiveness scale (SRS) scores of children with ASD. The fALFF values in the ROIs were reduced in children with ASD when compared to the TD group. In terms of the efferent connectivity from the ROIs to the whole brain, the ASD group exhibited increased connectivity in the right cingulate gyrus and decreased connectivity in the right superior temporal gyrus. Regarding the afferent connectivity from the whole brain to the ROIs, the ASD group displayed increased connectivity in the right globus pallidus and decreased connectivity in the right cerebellar Crus 1 area and left cingulate gyrus. Additionally, we demonstrated a positive correlation between effective connectivity derived from GCA and SRS scores. Impairments in social preference ASD children is linked to impaired effective connectivity in brain regions associated with social cognition, emotional responses, social rewards, and social decision-making. This finding further reveals the potential neuropathological mechanisms underlying ASD.

Deciphering Authentic Nociceptive Thalamic Responses in Rats.

The thalamus and its cortical connections play a pivotal role in pain information processing, yet the exploration of its electrophysiological responses to nociceptive stimuli has been limited. Here, in 2 experiments we recorded neural responses to nociceptive laser stimuli in the thalamic (ventral posterior lateral nucleus and medial dorsal nucleus) and cortical regions (primary somatosensory cortex [S1] and anterior cingulate cortex) within the lateral and medial pain pathways. We found remarkable similarities in laser-evoked brain responses that encoded pain intensity within thalamic and cortical regions. Contrary to the expected temporal sequence of ascending information flow, the recorded thalamic response (N1) was temporally later than its cortical counterparts, suggesting that it may not be a genuine thalamus-generated response. Importantly, we also identified a distinctive component in the thalamus, i.e., the early negativity (EN) occurring around 100 ms after the onset of nociceptive stimuli. This EN component represents an authentic nociceptive thalamic response and closely synchronizes with the directional information flow from the thalamus to the cortex. These findings underscore the importance of isolating genuine thalamic neural responses, thereby contributing to a more comprehensive understanding of the thalamic function in pain processing. Additionally, these findings hold potential clinical implications, particularly in the advancement of closed-loop neuromodulation treatments for neurological diseases targeting this vital brain region.

CRISPR-Cas9 knockdown of ESR1 in preoptic GABA-kisspeptin neurons suppresses the preovulatory surge and estrous cycles in female mice.

Evidence suggests that estradiol-sensing preoptic area GABA neurons are involved in the preovulatory surge mechanism necessary for ovulation. In vivo CRISPR-Cas9 editing was used to achieve a 60-70% knockdown in estrogen receptor alpha (ESR1) expression by GABA neurons located within the regions of the rostral periventricular area of the third ventricle (RP3V) and medial preoptic nuclei (MPN) in adult female mice. Mice exhibited variable reproductive phenotypes with the only significant finding being mice with bilateral ESR1 deletion in RP3V GABA neurons having reduced cFos expression in gonadotropin-releasing hormone (GnRH) neurons at the time of the surge. One sub-population of RP3V GABA neurons expresses kisspeptin. Re-grouping ESR1-edited mice on the basis of their RP3V kisspeptin expression revealed a highly consistent phenotype; mice with a near-complete loss of kisspeptin immunoreactivity displayed constant estrus and failed to exhibit surge activation but retained pulsatile luteinizing hormone (LH) secretion. These observations demonstrate that ESR1-expressing GABA-kisspeptin neurons in the RP3V are essential for the murine preovulatory LH surge mechanism.

Excitatory subtypes of the lateral amygdala neurons are differentially involved in regulation of synaptic plasticity and excitation/inhibition balance in aversive learning in mice.

The amygdala plays a crucial role in aversive learning. In Pavlovian fear conditioning, sensory information about an emotionally neutral conditioned stimulus (CS) and an innately aversive unconditioned stimulus is associated with the lateral amygdala (LA), and the CS acquires the ability to elicit conditioned responses. Aversive learning induces synaptic plasticity in LA excitatory neurons from CS pathways, such as the medial geniculate nucleus (MGN) of the thalamus. Although LA excitatory cells have traditionally been classified based on their firing patterns, the relationship between the subtypes and functional properties remains largely unknown. In this study, we classified excitatory cells into two subtypes based on whether the after-depolarized potential (ADP) amplitude is expressed in non-ADP cells and ADP cells. Their electrophysiological properties were significantly different. We examined subtype-specific synaptic plasticity in the MGN-LA pathway following aversive learning using optogenetics and found significant experience-dependent plasticity in feed-forward inhibitory responses in fear-conditioned mice compared with control mice. Following aversive learning, the inhibition/excitation (I/E) balance in ADP cells drastically changed, whereas that in non-ADP cells tended to change in the reverse direction. These results suggest that the two LA subtypes are differentially regulated in relation to synaptic plasticity and I/E balance during aversive learning.

A Developmental Switch in Cholinergic Mechanisms of Modulation in the Medial Nucleus of the Trapezoid Body.

The medial nucleus of the trapezoid body (MNTB) has been intensively investigated as a primary source of inhibition in brainstem auditory circuitry. MNTB-derived inhibition plays a critical role in the computation of sound location, as temporal features of sounds are precisely conveyed through the calyx of Held/MNTB synapse. In adult gerbils, cholinergic signaling influences sound-evoked responses of MNTB neurons via nicotinic acetylcholine receptors (nAChRs; Zhang et al., 2021) establishing a modulatory role for cholinergic input to this nucleus. However, the cellular mechanisms through which acetylcholine (ACh) mediates this modulation in the MNTB remain obscure. To investigate these mechanisms, we used whole-cell current and voltage-clamp recordings to examine cholinergic physiology in MNTB neurons from Mongolian gerbils (Meriones unguiculatus) of both sexes. Membrane excitability was assessed in brain slices, in pre-hearing (postnatal days 9-13) and post-hearing onset (P18-20) MNTB neurons during bath application of agonists and antagonists of nicotinic (nAChRs) and muscarinic receptors (mAChRs). Muscarinic activation induced a potent increase in excitability most prominently prior to hearing onset with nAChR modulation emerging at later time points. Pharmacological manipulations further demonstrated that the voltage-gated K+ channel KCNQ (Kv7) is the downstream effector of mAChR activation that impacts excitability early in development. Cholinergic modulation of Kv7 reduces outward K+ conductance and depolarizes resting membrane potential. Immunolabeling revealed expression of Kv7 channels as well as mAChRs containing M1 and M3 subunits. Together, our results suggest that mAChR modulation is prominent but transient in the developing MNTB and that cholinergic modulation functions to shape auditory circuit development.

Polioencephalopathy in Eurasier dogs.

Polioencephalopathies secondary to inborn errors of metabolism have been described in dogs, but few genetically characterized. Clinically and genetically characterize polioencephalopathy in a family of Eurasier dogs. Three Eurasier dogs (littermates) presented with early onset movement disorders (9 weeks in 2, 4-6 months in 1). Progressive gait abnormalities were detected in 2 of the dogs, persistent divergent strabismus in 1, whereas consciousness and behavior remained intact in all dogs. One dog was euthanized at 25 months. Video footage was assessed in all dogs, and Dogs 1 and 2 had examinations and investigations performed. Whole genome sequencing of Dog 1 and further genetic analyses in the family were performed. A cohort of 115 Eurasier controls was genotyped for specific variants. Episodes were characterized by generalized ataxia, as well as a hypermetric thoracic limb gait, dystonia, and irregular flexion and extension movements of the thoracic limbs. Magnetic resonance imaging of the brain in Dogs 1 and 2 identified symmetrical, bilateral T2 and fluid attenuated inversion recovery hyperintense, T1 hypo to isointense, nonenhancing lesions of the caudate nucleus, lateral and medial geniculate nuclei, thalamus, hippocampus, rostral colliculus and mild generalized brain atrophy. Genetic analyses identified a homozygous mitochondrial trans-2-enoyl-CoA reductase (MECR) missense variant in all 3 dogs, and a homozygous autophagy-related gene 4D (ATG4D) missense variant in Dogs 1 and 2. We describe a presumed hereditary and progressive polioencephalopathy in a family of Eurasier dogs. Further research is needed to establish the role of the MECR gene in dogs and the pathogenic effects of the detected variants.

Family history of dementia is associated with longer sleep duration and smaller volume of the thalamus in the PREVENT‐Dementia study

AbstractBackgroundThe relationship between sleep and dementia risk is complex, with both longer and shorter sleep duration being associated with cognitive decline. The thalamus has an important role in regulating the sleep‐wake cycle and structural changes may be a good marker of sleep abnormalities. Our aim was to investigate the association between dementia risk, sleep and the volume of thalamic nuclei.MethodWe analysed baseline data from PREVENT‐dementia, a multicentre, prospective cohort study of cognitively intact participants aged 40 to 59 years, who were stratified according to presence of the ApoE4 allele and parental family history of dementia (FH+). Sleep data was collected using the Pittsburgh Sleep Quality Index (PSQI) which measures subjective sleep quality, latency, duration, efficiency, disturbances, medication use and daytime dysfunction. T1‐weighted 3T MRI images were analysed using Freesurfer (version 7.1.0) to determine the volume of the thalamus and its subnuclei, controlling for total intracranial volume. The score on the centre for epidemiologic studies depression scale and the number of analgesic medications, were also used as covariates in the analysis to control for mood and pain. The data was analysed in R Studio using robust logistic regression.ResultComplete data was available for 594 participants. The total PSQI score was lower in FH+ subjects (p = 0.046) but was not associated with ApoE4 status. FH+ subjects had smaller volumes of mediodorsal medial (p = 0.03) and lateral (p = 0.03) nuclei, longer sleep duration (p = 0.02), and counterintuitively less sleep‐related daytime dysfunction (p = 0.01) compared to controls. In the FH+ group, larger pulvinar nucleus was associated with better sleep quality (r = ‐0.17, p = 0.002). In apoE4 non‐carriers, a larger thalamus (r = ‐0.12, p = 0.02) and larger centromedian nucleus (r = ‐0.13, p = 0.01) were both associated with a lower total PSQI score. They also had an association between larger pulvinar (r = ‐0.11, p = 0.04) and centromedian (r = ‐0.14, p = 0.007) nuclei and increased sleep efficiency.ConclusionMiddle‐aged subjects with a FH+ had longer sleep duration and smaller thalamic volumes which may represent early neurodegenerative changes. Furthermore, we found an association between larger thalamic nuclei and better sleep variables, especially in ApoE4 non‐carriers, indicating that the thalamus may be an important imaging correlate of sleep quality.