1.Immunoregulatory role of the gut microbiota in inflammatory depression

DOI: 10.1038/s41467-024-47273-w

https://www.nature.com/articles/s41467-024-47273-w

Inflammatory depression, a treatment-resistant subtype, may be linked to gut microbiota-induced low-grade inflammation. In a trial, patients with this form of depression exhibited altered gut microbiota composition, with higher Bacteroides and lower Clostridium levels, along with abnormal butanoate metabolism. Fecal microbiota transplantation (FMT) and probiotic supplementation in animal models revealed that changes in gut microbiota composition led to increased inflammation and intestinal permeability, as well as depressive and anxiety-like behaviors. Administration of Clostridium butyricum normalized gut microbiota, reduced inflammation, and exhibited antidepressant effects. These findings suggest a potential causal relationship between gut microbiota-derived inflammatory processes and neuroinflammation in inflammatory depression.

2.Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer's pathology

DOI: 10.1038/s41467-024-47028-7

https://www.nature.com/articles/s41467-024-47028-7

Dysfunction in fast-spiking parvalbumin interneurons (PV-INs) may represent an early pathological event in Alzheimer's Disease (AD). To understand early proteomic changes in PV-INs, we utilized cell-type-specific in-vivo biotinylation of proteins (CIBOP) combined with mass spectrometry. This approach revealed distinctive PV-IN proteomic profiles characterized by heightened metabolic and translational activity, and enrichment of proteins linked to AD risk and cognitive resilience. PV-IN proteins correlated with cognitive decline in humans and neuropathology in both humans and a mouse model of Aβ pathology. Additionally, early Aβ pathology in PV-INs showed increased mitochondrial activity, synaptic and cytoskeletal disruption, and decreased mTOR signaling, which were not evident in whole-brain proteomes. Our findings also confirmed pre-synaptic defects in PV-to-excitatory neurotransmission, underscoring the significance of PV-INs in AD pathogenesis and cognitive resilience.

3.Neural signatures of indirect pathway activity during subthalamic stimulation in Parkinson's disease

DOI: 10.1038/s41467-024-47552-6

https://www.nature.com/articles/s41467-024-47552-6

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease induces evoked resonant neural activity (ERNA), linked to treatment efficacy. This study explores ERNA's neuronal and synaptic bases. ERNA represents engagement of the basal ganglia's indirect pathway network, with each ERNA peak associated with STN neuronal inhibition. Temporal dynamics and circuit architecture of ERNA were characterized. ERNA was localized to the dorsal STN, and its spatial relevance to DBS outcome was assessed. Fiber activation profiles associated with ERNA were identified. These findings provide insights into the mechanistic underpinnings of DBS-mediated therapeutic effects in Parkinson's disease.

4.Latent neural population dynamics underlying breathing, opioid-induced respiratory depression and gasping

DOI: 10.1038/s41593-023-01520-3

https://www.nature.com/articles/s41593-023-01520-3

Breathing, a fundamental physiological process, relies on the coordinated activity of medullary nuclei in the ventral respiratory column (VRC). Despite the rhythmic properties of individual VRC nuclei being well-understood, studying the entire population simultaneously has been challenging. In this study, we employed high-density electrophysiology, opto-tagging, and histological reconstruction to characterize over 15,000 medullary units. Population dynamics analysis revealed consistent rotational trajectories through a low-dimensional neural manifold. These rotations remained robust even during opioid-induced respiratory depression. However, during severe hypoxia-induced gasping, VRC dynamics shifted from rotational to all-or-none, ballistic efforts. These findings offer insights into how large, heterogeneous populations of neurons govern the vital behavior of breathing and respond to various perturbations.

5.Pharmacogenomic overlap between antidepressant treatment response in major depression & antidepressant associated treatment emergent mania in bipolar disorder

DOI: 10.1038/s41398-024-02798-y

https://www.nature.com/articles/s41398-024-02798-y

This study investigated the relationship between antidepressant response in major depressive disorder (MDD) and treatment-emergent mania (TEM) in bipolar disorder (BD). Despite inconclusive evidence, antidepressants (ADs) are often prescribed for BD depressive phases, leading to inadequate response or mood destabilization. Conducting a genome-wide association study (GWAS) and polygenic score analysis, no significant variants were found, but a higher polygenic score for antidepressant response in MDD correlated with increased odds of TEM in BD. This suggests a potential genetic link between antidepressant response and TEM. Larger studies with transdiagnostic depressed cohorts are needed to elucidate neurobiological mechanisms underlying the spectrum of depression improvement and TEM emergence.