Adolescent cerebellar nuclei manipulation alters reversal learning and perineuronal net intensity independently in male and female mice.

The cerebellum, identified to be active during cognitive and social behavior, has multisynaptic connections through the cerebellar nuclei (CN) and thalamus to cortical regions, yet formation and modulation of these pathways are not fully understood. Perineuronal nets (PNNs) respond to changes in local cellular activity and emerge during development. PNNs are implicated in learning and neurodevelopmental disorders, but their role in the CN during development is unknown.

Multimodal evidence for cerebellar influence on cortical development in autism: structural growth amidst functional disruption.

Despite perinatal damage to the cerebellum being one of the highest risk factors for later being diagnosed with autism spectrum disorder (ASD), it is not yet clear how the cerebellum might influence the development of cerebral cortex and whether this co-developmental process is distinct between neurotypical and ASD children. Leveraging a large structural brain MRI dataset of neurotypical children and those diagnosed with ASD, we examined whether structural variation in cerebellar tissue across individuals was correlated with neocortical variation during development, including the thalamus as a coupling factor. We found that the thalamus plays a distinct role in moderating cerebro-cerebellar structural coordination in ASD.

Restoring cerebellar-dependent learning.

Behavioral and pharmaceutical interventions reverse defects associated with increased cerebellar long-term depression in a mouse model of Fragile X syndrome.

An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission.

Recombinant adeno-associated viruses (AAVs) allow rapid and efficient gene delivery to the nervous system, are widely used in neuroscience research, and are the basis of FDA-approved neuron-targeting gene therapies. Here we find that an innate immune response to the AAV genome reduces dendritic length and complexity and disrupts synaptic transmission in mouse somatosensory cortex. Dendritic loss is apparent 3 weeks after injection of experimentally relevant viral titers, is not restricted to a particular capsid serotype, transgene, promoter, or production facility, and cannot be explained by responses to surgery or transgene expression.

Cognitive-Affective Functions of the Cerebellum.

The cerebellum, traditionally associated with motor coordination and balance, also plays a crucial role in various aspects of higher-order function and dysfunction. Emerging research has shed light on the cerebellum's broader contributions to cognitive, emotional, and reward processes. The cerebellum's influence on autonomic function further highlights its significance in regulating motivational and emotional states.

Cerebellar contributions to a brainwide network for flexible behavior in mice.

The cerebellum regulates nonmotor behavior, but the routes of influence are not well characterized. Here we report a necessary role for the posterior cerebellum in guiding a reversal learning task through a network of diencephalic and neocortical structures, and in flexibility of free behavior. After chemogenetic inhibition of lobule VI vermis or hemispheric crus I Purkinje cells, mice could learn a water Y-maze but were impaired in ability to reverse their initial choice.

Local and systemic administration of AAV vectors with alphaherpesvirus latency-associated promoter 2 drives potent transgene expression in mouse liver, kidney, and skeletal muscle.

Adeno-associated virus (AAV) has great potential as a source of treatments for conditions that might respond to potent and ubiquitous transgene expression. However, among its drawbacks, the genetic "payload" of AAV vectors is limited to <4.9 kb and some commonly used gene promoters are sizeable and susceptible to transcriptional silencing.

Single-Cell Quantification of Triple-AAV Vector Genomes Coexpressed in Neurons.

Adeno-associated viruses (AAVs) are one of the most widely used types of viral vectors for research and gene therapy. AAV vectors are safe, have a low immunogenic profile, and provide efficient and long-term transgene expression in a variety of tissues and organs targeted by a specific serotype. Despite these unique features, therapeutic applications, as well as basic research studies, of AAVs have been limited by their packaging capacity of less than 5 kb.

Automated high-throughput mouse transsynaptic viral tracing using iDISCO+ tissue clearing, light-sheet microscopy, and BrainPipe.

Transsynaptic viral tracing requires tissue sectioning, manual cell counting, and anatomical assignment, all of which are time intensive. We describe a protocol for BrainPipe, a scalable software for automated anatomical alignment and object counting in light-sheet microscopy volumes. BrainPipe can be generalized to new counting tasks by using a new atlas and training a neural network for object detection.

Deep phenotyping reveals movement phenotypes in mouse neurodevelopmental models.

Background: Repetitive action, resistance to environmental change and fine motor disruptions are hallmarks of autism spectrum disorder (ASD) and other neurodevelopmental disorders, and vary considerably from individual to individual. In animal models, conventional behavioral phenotyping captures such fine-scale variations incompletely. Here we observed male and female C57BL/6J mice to methodically catalog adaptive movement over multiple days and examined two rodent models of developmental disorders against this dynamic baseline.

The influence of estrogen receptor α signaling independent of the estrogen response element on avoidance behavior, social interactions, and palatable ingestive behavior in female mice.

Women are vulnerable to developing mental disorders that are associated with circulating estrogens. Estrogens, especially 17β-estradiol (E2), have a wide array of effects on the brain, affecting many behavioral endpoints associated with mental illness. By using a total estrogen receptor (ER) α knockout (KO), an ERα knock in/knock out (KIKO) that lacks a functional DNA-binding domain, and wild type (WT) controls treated with either oil or E2, we evaluated ERα signaling, dependent and independent of the estrogen response element (ERE), on avoidance behavior, social interactions and memory, and palatable ingestive behavior using the open field test, the elevated plus maze, the light dark box, the 3-chamber test, and palatable feeding.

Homologous organization of cerebellar pathways to sensory, motor, and associative forebrain.

Cerebellar outputs take polysynaptic routes to reach the rest of the brain, impeding conventional tracing. Here, we quantify pathways between the cerebellum and forebrain by using transsynaptic tracing viruses and a whole-brain analysis pipeline. With retrograde tracing, we find that most descending paths originate from the somatomotor cortex.

Novel tool to quantify with single-cell resolution the number of incoming AAV genomes co-expressed in the mouse nervous system.

Adeno-associated viral (AAV) vectors are an established and safe gene delivery tool to target the nervous system. However, the payload capacity of <4.9 kb limits the transfer of large or multiple genes.

Small Alphaherpesvirus Latency-Associated Promoters Drive Efficient and Long-Term Transgene Expression in the CNS.

Recombinant adeno-associated viruses (rAAVs) are used as gene therapy vectors to treat central nervous system (CNS) diseases. Despite their safety and broad tropism, important issues need to be corrected such as the limited payload capacity and the lack of small gene promoters providing long-term, pan-neuronal transgene expression in the CNS. Commonly used gene promoters are relatively large and can be repressed a few months after CNS transduction, risking the long-term performance of single-dose gene therapy applications.

The p75NTR Influences Cerebellar Circuit Development and Adult Behavior via Regulation of Cell Cycle Duration of Granule Cell Progenitors.

Development of brain circuitry requires precise regulation and timing of proliferation and differentiation of neural progenitor cells. The p75 neurotrophin receptor (p75NTR) is highly expressed in the proliferating granule cell precursors (GCPs) during development of the cerebellum. In a previous paper, we showed that proNT3 promoted GCP cell cycle exit via p75NTR.

Normal cognitive and social development require posterior cerebellar activity.

Cognitive and social capacities require postnatal experience, yet the pathways by which experience guides development are unknown. Here we show that the normal development of motor and nonmotor capacities requires cerebellar activity. Using chemogenetic perturbation of molecular layer interneurons to attenuate cerebellar output in mice, we found that activity of posterior regions in juvenile life modulates adult expression of eyeblink conditioning (paravermal lobule VI, crus I), reversal learning (lobule VI), persistive behavior and novelty-seeking (lobule VII), and social preference (crus I/II).

Increased nicotine response in iPSC-derived human neurons carrying the CHRNA5 N398 allele.

Genetic variation in nicotinic receptor alpha 5 (CHRNA5) has been associated with increased risk of addiction-associated phenotypes in humans yet little is known the underlying neural basis. Induced pluripotent stem cells (iPSCs) were derived from donors homozygous for either the major (D398) or the minor (N398) allele of the nonsynonymous single nucleotide polymorphism (SNP), rs16969968, in CHRNA5. To understand the impact of these nicotinic receptor variants in humans, we differentiated these iPSCs to dopamine (DA) or glutamatergic neurons and then tested their functional properties and response to nicotine.

Ketogenic diet exposure during the juvenile period increases social behaviors and forebrain neural activation in adult Engrailed 2 null mice.

Prolonged consumption of ketogenic diets (KD) has reported neuroprotective benefits. Several studies suggest KD interventions could be useful in the management of neurological and developmental disorders. Alterations in the Engrailed (En) genes, specifically Engrailed 2 (En2), have neurodevelopmental consequences and produce autism-related behaviors.

Intermittent Fasting Promotes Fat Loss With Lean Mass Retention, Increased Hypothalamic Norepinephrine Content, and Increased Neuropeptide Y Gene Expression in Diet-Induced Obese Male Mice.

Clinical studies indicate alternate-day, intermittent fasting (IMF) protocols result in meaningful weight loss in obese individuals. To further understand the mechanisms sustaining weight loss by IMF, we investigated the metabolic and neural alterations of IMF in obese mice. Male C57/BL6 mice were fed a high-fat diet (HFD; 45% fat) ad libitum for 8 weeks to promote an obese phenotype.

Dietary-induced binge eating increases prefrontal cortex neural activation to restraint stress and increases binge food consumption following chronic guanfacine.

Binge eating is a prominent feature of bulimia nervosa and binge eating disorder. Stress or perceived stress is an often-cited reason for binge eating. One notion is that the neural pathways that overlap with stress reactivity and feeding behavior are altered by recurrent binge eating.

Drug safety evaluation of naltrexone/bupropion for the treatment of obesity.

Introduction: Obesity is a known health risk for the development of several preventable diseases. Obesity-related metabolic alterations negatively impact different physiological mechanisms, which supports the rationale for the use of combined drug therapy. Naltrexone is an opioid antagonist for the treatment of opioid and alcohol dependency, whereas bupropion is a norepinephrine/dopamine reuptake inhibitor used to treat depression and smoking cessation.

Binge-like eating attenuates nisoxetine feeding suppression, stress activation, and brain norepinephrine activity.

Stress is often associated with binge eating. A critical component of the control of stress is the central norepinephrine system. We investigated how dietary-induced binge eating alters central norepinephrine and related behaviors.