Age-related cognitive decline in learning and decision-making may arise from increased variability of neural responses. Here, we investigated how ageing affects behavioral and neural variability by recording >18,000 neurons across 16 brain regions (including cortex, hippocampus, thalamus, midbrain, and basal ganglia) in younger and older mice performing a visual decision-making task. Older mice showed more variable response times, reproducing a common finding in human ageing studies. Ageing globally increased firing rates, post-stimulus neural variability (quantified using the Fano Factor), and decreased 'variability quenching' (the reduction in neural variability upon stimulus presentation). Older animals showed higher overall firing rates across areas of visual and motor cortex, striatum, midbrain, and hippocampus, but lower firing rates in thalamic areas. Age-related attenuation in stimulus-induced variability quenching was most prominent in visual and motor cortex, striatum, and thalamic area. These findings show how large-scale neural recordings can help uncover regional specificity of ageing effects in single neurons, improving our understanding of the neural basis of age-related cognitive decline.

Parkinson's disease (PD) is characterized by progressive neurodegeneration, which is associated with motor and non-motor symptoms. Dopamine replacement therapy can remediate motor symptoms, but can also cause impulse control disorder (ICD), characterized by pathological gambling, hypersexuality, and/or compulsive shopping. Approximately 14-40% of all medicated PD patients suffer from ICD. Despite the high prevalence of ICD in medicated PD patients, we know little of its mechanisms, and the main therapeutic strategy is reducing or eliminating dopamine agonist medication. Human imaging studies suggest that the input nucleus of the basal ganglia, the striatum, may be a critical site of circuit dysfunction in ICD. To explore the cellular and circuit mechanisms of ICD, we developed a mouse model in which we administered the dopamine D2/3 agonist pramipexole to parkinsonian and healthy control mice. ICD-like behavior was assessed using a delay discounting task. Delay discounting is a normal cognitive phenomenon, in which the value of a reward decreases according to the time needed to wait for it. Impulsivity is measured as the preference for immediate (small) over delayed (large) rewards. We combined this mouse model with chemogenetics and in vivo optically-identified single-unit recordings to examine how dopamine agonists act on vulnerable striatal circuitry to mediate impulsive decision-making. We found that in parkinsonian mice, therapeutic doses of dopamine D2/3R or D1R agonists drove more pronounced delay discounting, reminiscent of what has been reported in PD/ICD patients on medication. In contrast, healthy mice did not become more impulsive when given the same dose of dopamine agonist. The clinically relevant dopamine D2/3R agonist pramipexole induced marked bidirectional changes in the firing of striatal direct and indirect pathway neurons in parkinsonian mice. Chronic pramipexole treatment potentiated these changes in striatal physiology and decision-making behavior. Furthermore, chemogenetic excitation of direct pathway striatal neurons or inhibition of indirect pathway neurons induced impulsive decision making in the absence of dopamine agonists. These findings indicate that abnormal striatal activity plays a causal role in mediating ICD-like behaviors. Together, they provide a robust mouse model and insights into ICD pathophysiology.

Repetitive behaviors are cardinal features of many brain disorders, including autism spectrum disorder (ASD). We previously associated dysfunction of striatal cholinergic interneurons (SCINs) with repetitive behaviors in a mouse model based on conditional deletion of the ASD-related gene Tshz3 in cholinergic neurons (Chat-cKO). Here, we provide evidence linking SCIN abnormalities to the unique organization of the striatum into striosome and matrix compartments, whose imbalances are implicated in several pathological conditions. Chat-cKO mice exhibit an altered relationship between the embryonic birthdate of SCINs and their adult striosome-matrix distribution, leading to an increased proportion of striosomal SCINs. In addition, the ratio of striosomal SCINs with slow-irregular vs. sustained-regular firing is increased, which translates into decreased activity, further stressing the striosome-matrix imbalance. These findings provide novel insights into the pathogenesis of ASD-related stereotyped behaviors by pointing to abnormal developmental compartmentalization and activity of SCINs as a substrate.

Cell transplantation offers a promising approach for treating Parkinson's disease (PD), but the limited survival of transplanted cells remains a major challenge. Reactive astrocytes, abundant in PD brains, may exacerbate this issue. GLP1R agonists, like semaglutide, are shown to inhibit reactive astrocytes in PD models. This study explores whether semaglutide could enhance the survival of transplanted neural stem cells (NSCs) in PD treatment. Six-hydroxydopamine-induced PD mouse models are used, with midbrain-derived NSCs transplanted into the lesioned striatum. Semaglutide is administered every other day for four weeks. In vivo imaging tracks the survival and distribution of DiD-labeled NSCs, while differentiation and astrocyte phenotypic changes are examined. Results show that semaglutide combined with NSC transplantation improves motor function. The mean fluorescence photon flux of mice transplanted with DiD-labeled NSCs alone is 0.8192 × 10, compared to 3.258 × 10 in those receiving both semaglutide and NSCs. Additionally, semaglutide reduces C3 reactive astrocytes (previously A1 reactive astrocytes) in the striatum. Co-culture experiments indicate that C3 reactive astrocytes hinder NSCs differentiation. RNA-seq reveals enriched inflammatory factors in C3 astrocytes. Semaglutide combined with NSCs transplantation may enhance PD treatment partly by inhibiting C3 reactive astrocytes and promoting the survival and differentiation of transplanted cells.

Converging evidence from neuroimaging studies and genome-wide association study (GWAS) suggests the involvement of prefrontal cortex (PFC) and striatum dysfunction in the pathophysiology of anorexia nervosa (AN). However, identifying the causal role of circuit-specific genes in the development of the AN-like phenotype remains challenging and requires the combination of novel molecular tools and preclinical models.