James N. Samsom

Obesity is a worldwide health crisis, with unhealthy diet as a major contributor. Comorbid neuropsychiatric conditions such as depression and anxiety are associated with obesity. Since obesity is a pro-inflammatory state, chronic neuroinflammation may mediate obesity and neuropsychiatric comorbidity. We used RNA-seq to provide a single-cell resolution transcriptome of brain immune cells using long-term high-fat diet (HFD) to model obesity in male mice. HFD mice exhibited depression and anxiety-like behavior. We observed a shift towards increased proportions of lipid droplet-accumulating microglia (LDAM) in the long-term HFD brain. By in-depth characterization of the transcriptional signature of LDAM, we identified that ACSL1, a key regulator of lipid droplet biogenesis, was highly expressed in LDAM induced by HFD. Finally, we demonstrated that ACSL1 inhibition reduced lipid droplets deposition in microglia exposed to free fatty acids (FFA). Our findings provide a comprehensive view of the molecular changes in brain immune cells associated with HFD, suggesting a link between microglial lipid droplet accumulation and neurological comorbidities induced by obesity.

Depression is one of the most common mental disorders, but its etiology remains poorly understood. Neuronal nitric oxide synthase (nNOS) has been implicated in depression, but the role of nNOS-expressing neurons is still unknown. We used chemogenetic strategies to show that nNOS-expressing neurons in the medial prefrontal cortex (mPFC) are essential for depression-related behaviors. Using electrophysiology, we determined that mPFC nNOS-expressing neurons receive projections from the posterior subregion of the paraventricular thalamic nucleus (pPVT). We show that excitatory projections from the pPVT onto mPFC nNOS-expressing neurons regulate depression-related behaviors. We further explore a mechanism in which activation of mPFC nNOS-expressing neurons leads to the subsequent release of nitric oxide (NO), which enhances the nitrosylation of cyclin-dependent kinase 5 (CDK5). Our data suggest a mechanism for depression involving excitatory pPVT projections onto nNOS-expressing neurons in the mPFC that represents a potential target for future treatments.

Protein interacting with C-kinase 1 (PICK1) is important for synaptic plasticity through directing transport of glutamate receptors and other proteins. PICK1 gene variants have been associated with schizophrenia. To examine the role of PICK1 in schizophrenia-related behaviors, mice with a mutation in the PICK1 lipid-interacting BAR domain were characterized. Male Pick1-S262T mice had disrupted AMPA receptor (AMPAR) subunit GluA1 and GluA2 protein expression in the hippocampus and prefrontal cortex (PFC). Young adult, but not juvenile (P21), Pick1-S262T mice showed decreased hippocampal synaptic transmission and deficits in long-term depression (LTD). Mutant males also had deficits in reversal learning in the Morris water maze (MWM). These observations suggest that the Pick1-S262T mutation affects AMPAR trafficking, disrupting synaptic transmission and plasticity, as well as cognitive flexibility, a core neuropsychological deficit in schizophrenia. This work suggests possible mechanisms by which a known schizophrenia susceptibility gene could contribute to clinical features of the disorder.

While most research and treatments for multiple sclerosis (MS) focus on autoimmune reactions causing demyelination, it is possible that neurodegeneration precedes the autoimmune response. Hence, glutamate receptor antagonists preventing excitotoxicity showed promise in MS animal models, though blocking glutamate signaling prevents critical neuronal functions. This study reports the discovery of a small molecule that prevents AMPA-mediated excitotoxicity by targeting an allosteric binding site. A machine learning approach was used to screen for small molecules targeting the AMPA receptor GluA2 subunit. The lead candidate has potent effects in restoring neurological function and myelination while reducing the immune response in experimental autoimmune encephalitis and cuprizone MS mouse models without affecting basal neurotransmission or learning and memory. These findings facilitate development of a treatment for MS with a different mechanism of action than current immune modulatory drugs and avoids important off-target effects of glutamate receptor antagonists. This class of MS therapeutics could be useful as an alternative or complementary treatment to existing therapies.