Single-Nucleus Transcriptomics Identifies Neuroblast Migration Programs Sensitive to Reelin and Cannabis in the Adolescent Nucleus Accumbens.

The interplay between cannabis exposure during adolescence and genetic predisposition has been linked to increased vulnerability to psychiatric disorders. To investigate the molecular underpinnings of this interaction, we performed single-nucleus RNA sequencing of the nucleus accumbens (NAc) in a mouse model of haploinsufficiency, a genetic risk factor for psychiatric disorders, following adolescent exposure to tetrahydrocannabinol (THC), the primary psychoactive component of cannabis. We identified a gene co-expression network influenced by both genotype and THC, enriched in genes associated with human psychiatric disorders and predominantly expressed in a GABAergic neuroblast subpopulation.

The attenuation of activity-based anorexia by obese adipose tissue transplant is AgRP neuron-dependent.

Anorexia nervosa (AN) is an eating disorder observed primarily in girls and women, and is characterized by a low body mass index, hypophagia, and hyperactivity. The activity-based anorexia (ABA) paradigm models aspects of AN, and refers to the progressive weight loss, hypophagia, and hyperactivity developed by rodents exposed to time-restricted feeding and running wheel access. Recent studies identified white adipose tissue (WAT) as a primary location of the 'metabolic memory' of prior obesity, and implicated WAT-derived signals as drivers of recidivism to obesity following weight loss.

TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis.

The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis are not fully understood. Here, we show that deletion of a nuclear seven transmembrane protein, TM7SF3, accelerates HSC activation in liver organoids, primary human HSCs, and in vivo in metabolic-dysfunction-associated steatohepatitis (MASH) mice, leading to activation of the fibrogenic program and HSC proliferation. Thus, TM7SF3 knockdown promotes alternative splicing of the Hippo pathway transcription factor, TEAD1, by inhibiting the splicing factor heterogeneous nuclear ribonucleoprotein U (hnRNPU).

Adipose tissue macrophages secrete small extracellular vesicles that mediate rosiglitazone-induced insulin sensitization.

The obesity epidemic continues to worsen worldwide, driving metabolic and chronic inflammatory diseases. Thiazolidinediones, such as rosiglitazone (Rosi), are PPARγ agonists that promote 'M2-like' adipose tissue macrophage (ATM) polarization and cause insulin sensitization. As ATM-derived small extracellular vesicles (ATM-sEVs) from lean mice are known to increase insulin sensitivity, we assessed the metabolic effects of ATM-sEVs from Rosi-treated obese male mice (Rosi-ATM-sEVs).

Social isolation recruits amygdala-cortical circuitry to escalate alcohol drinking.

How do social factors impact the brain and contribute to increased alcohol drinking? We found that social rank predicts alcohol drinking, where subordinates drink more than dominants. Furthermore, social isolation escalates alcohol drinking, particularly impacting subordinates who display a greater increase in alcohol drinking compared to dominants. Using cellular resolution calcium imaging, we show that the basolateral amygdala-medial prefrontal cortex (BLA-mPFC) circuit predicts alcohol drinking in a rank-dependent manner, unlike non-specific BLA activity.

Sex differences in risk-based decision-making and the modulation of risk preference by dopamine-2 like receptors in rats.

Heightened risk-based decision-making is observed across several neuropsychiatric disorders including schizophrenia, bipolar disorder, and Parkinson's disease, yet no treatments exist that effectively normalize this aberrant behavior. Preclinical risk-based decision-making paradigms have identified the important modulatory roles of dopamine and sex in the performance of such tasks, though specific task parameters may alter such effects (e.g.

Targeting Clic1 for the treatment of obesity: A novel therapeutic strategy to reduce food intake and body weight.

Objective: Despite great advances in obesity therapeutics in recent years, there is still a need to identify additional therapeutic targets for the treatment of this disease. We previously discovered a signature of genes, including Chloride intracellular channel 1 (Clic1), whose expression was associated with drug-induced weight gain, and in these studies, we assess the effect of Clic1 inhibition on food intake and body weight in mice.

Methods: We studied the impact of Clic1 inhibition in mouse models of binge-eating, diet-induced obese mice and genetic models of obesity (Magel2 KO mice).

Nuclear receptor 5A2 regulation of Agrp underlies olanzapine-induced hyperphagia.

Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia.

Antipsychotic-induced weight gain and metabolic effects show diurnal dependence and are reversible with time restricted feeding.

Antipsychotic drugs (AP) are highly efficacious treatments for psychiatric disorders but are associated with significant metabolic side-effects. The circadian clock maintains metabolic homeostasis by sustaining daily rhythms in feeding, fasting and hormone regulation but how circadian rhythms interact with AP and its associated metabolic side-effects is not well-known. We hypothesized that time of AP dosing impacts the development of metabolic side-effects.

Neurotensin orchestrates valence assignment in the amygdala.

The ability to associate temporally segregated information and assign positive or negative valence to environmental cues is paramount for survival. Studies have shown that different projections from the basolateral amygdala (BLA) are potentiated following reward or punishment learning. However, we do not yet understand how valence-specific information is routed to the BLA neurons with the appropriate downstream projections, nor do we understand how to reconcile the sub-second timescales of synaptic plasticity with the longer timescales separating the predictive cues from their outcomes.

Cortical ensembles orchestrate social competition through hypothalamic outputs.

Most social species self-organize into dominance hierarchies, which decreases aggression and conserves energy, but it is not clear how individuals know their social rank. We have only begun to learn how the brain represents social rank and guides behaviour on the basis of this representation. The medial prefrontal cortex (mPFC) is involved in social dominance in rodents and humans.

Activity of Cerebellar Nuclei Neurons Correlates with ZebrinII Identity of Their Purkinje Cell Afferents.

Purkinje cells (PCs) in the cerebellar cortex can be divided into at least two main subpopulations: one subpopulation that prominently expresses ZebrinII (Z+), and shows a relatively low simple spike firing rate, and another that hardly expresses ZebrinII (Z-) and shows higher baseline firing rates. Likewise, the complex spike responses of PCs, which are evoked by climbing fiber inputs and thus reflect the activity of the inferior olive (IO), show the same dichotomy. However, it is not known whether the target neurons of PCs in the cerebellar nuclei (CN) maintain this bimodal distribution.

Corticotropin-releasing factor increases Purkinje neuron excitability by modulating sodium, potassium, and Ih currents.

Corticotropin-releasing factor (CRF) is a neuromodulator closely associated with stress responses. It is synthesized and released in the central nervous system by various neurons, including neurons of the inferior olive. The targets of inferior olivary neurons, the cerebellar Purkinje neurons (PNs), are endowed with CRF receptors.

In and out of the loop: external and internal modulation of the olivo-cerebellar loop.

Cerebellar anatomy is known for its crystal like structure, where neurons and connections are precisely and repeatedly organized with minor variations across the Cerebellar Cortex. The olivo-cerebellar loop, denoting the connections between the Cerebellar cortex, Inferior Olive and Cerebellar Nuclei (CN), is also modularly organized to form what is known as the cerebellar module. In contrast to the relatively organized and static anatomy, the cerebellum is innervated by a wide variety of neuromodulator carrying axons that are heterogeneously distributed along the olivo-cerebellar loop, providing heterogeneity to the static structure.