Salameh, J. | bioRxiv Science

bioRxiv2023

VIP interneurons regulate cortical size tuning and visual perception

Local cortical circuit function is regulated by diverse populations of GABAergic interneurons with distinct properties and extensive interconnectivity. Inhibitory-to-inhibitory interactions between interneuron populations may play key roles in shaping circuit operation according to behavioral context. A specialized population of GABAergic interneurons that co-express vasoactive intestinal peptide (VIP-INs) are activated during arousal and locomotion and innervate other local interneurons and pyramidal neurons. Although modulation of VIP-IN activity by behavioral state has been extensively studied, their role in regulating information processing and selectivity is less well understood. Using a combination of cellular imaging, short and long-term manipulation, and perceptual behavior, we examined the impact of VIP-INs on their synaptic target populations in the primary visual cortex of awake behaving mice. We find that loss of VIP-IN activity alters the behavioral state-dependent modulation of somatostatin-expressing interneurons (SST-INs) but not pyramidal neurons (PNs). In contrast, reduced VIP-IN activity disrupts visual feature selectivity for stimulus size in both populations. Inhibitory-to inhibitory interactions thus directly shape the selectivity of GABAergic interneurons for sensory stimuli. Moreover, the impact of VIP-IN activity on perceptual behavior varies with visual context and is more acute for small than large visual cues. VIP-INs thus contribute to both state-dependent modulation of cortical circuit activity and sensory context-dependent perceptual performance.

neuroscience↗

bioRxiv2021

Low-level overexpression of wild type TDP-43 causes late-onset, progressive neurodegeneration and paralysis in mice

Modestly increased expression of transactive response DNA binding protein (TDP-43) gene have been reported in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neuromuscular diseases. However, whether this modest elevation triggers neurodegeneration is not known. Although high levels of TDP-43 overexpression have been modeled in mice and shown to cause early death, models with low-level overexpression that mimic the human condition have not been established. In this study, transgenic mice overexpressing wild type TDP-43 at less than 60% above the endogenous CNS levels were constructed, and their phenotypes analyzed by a variety of techniques, including biochemical, molecular, histological, behavioral techniques and electromyography. The TDP-43 transgene was expressed in neurons, astrocytes, and oligodendrocytes in the cortex and predominantly in astrocytes and oligodendrocytes in the spinal cord. The mice developed a reproducible progressive weakness ending in paralysis in mid-life. Detailed analysis showed [~]30% loss of large pyramidal neurons in the layer V motor cortex; in the spinal cord, severe demyelination was accompanied by oligodendrocyte injury, protein aggregation, astrogliosis and microgliosis, and elevation of neuroinflammation. Surprisingly, there was no loss of lower motor neurons in the lumbar spinal cord despite the complete paralysis of the hindlimbs. However, denervation was detected at the neuromuscular junction. These results demonstrate that low-level TDP-43 overexpression can cause diverse aspects of ALS, including late-onset and progressive motor dysfunction, neuroinflammation, and neurodegeneration. Our findings suggest that persistent modest elevations in TDP-43 expression can lead to ALS and other neurological disorders involving TDP-43 proteinopathy. Because of the predictable and progressive clinical paralytic phenotype, this transgenic mouse model will be useful in preclinical trial of therapeutics targeting neurological disorders associated with elevated levels of TDP-43.

genetics↗