Biology subjects

Cain, M.

Publications and source records attributed to Cain, M..

4 recordsLinked to original sources

bioRxiv2023

Population coding of distinct categories of behavior in the frontal eye field

Brain regions frequently contribute to the control of diverse behaviors. Within these regions, individual neurons often respond to various motor tasks, suggesting that the ability to control multiple behaviors is rooted in the organization of neuronal populations. To study this organization, we examined how the frontal eye field (FEF) encodes distinct behaviors by recording the activity of 1200 neurons during various eye movement tasks in two female fascicularis monkeys. We focused on three behaviors: smooth pursuit, pursuit suppression, and saccades. We found that single neurons tended to respond in all three tasks, thus challenging the notion that the FEF is organized into task-specific clusters. We then identified the low-dimensional subspaces that contained most of the population activity during each behavior and quantified the extent of overlap between these spaces across behaviors. Population activity during pursuit and pursuit suppression exhibited a substantial overlap, with highly correlated directional tuning at the single-neuron level, as reflected by similar outcomes for the population decoders. These distinct behaviors combined with similar encoding suggest that the suppression of movement occurs mostly downstream from the FEF. By contrast, pursuit and saccades mostly occupied orthogonal subspaces, prompting an independent linear readout of saccades and pursuit. Thus overall, these results indicate that distinct behaviors can exhibit either separate or overlapping population codes within a specific brain region, hence emphasizing the importance of the system-level organization of behavior. Significance statementHow do brain areas control multiple behaviors? We investigated the organization of the FEF in monkeys during three different types of eye movements: smooth pursuit, pursuit suppression, and saccades. We found that individual neurons tended to respond to all three tasks, thus challenging a task-specific FEF cluster organization. Further, the low-dimensional subspaces that contained most of the population activity during pursuit and pursuit suppression overlapped substantially, implying that movement suppression occurs downstream from the FEF. In contrast, pursuit and saccades occupied orthogonal subspaces, prompting independent linear readouts. These results underscore the importance of adopting a system-level perspective to comprehend how diverse behaviors are encoded in the brain.

neuroscience↗

bioRxiv2020

Pharmacologic inhibition of Protein Kinase C α and Protein Kinase C β halts renal function decline indirectly, by blunting hyperphagia, and directly reduces adiposity in the ZSF1 rat model of type 2 diabetes

Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences. Despite advances that address some of the metabolic aspects of T2D, for many patients these approaches do not sufficiently control the disease. As a result, an emerging therapeutic strategy is to target the pathobiological mechanisms downstream of T2D metabolic derangement that can result in organ damage, morbidity, and mortality in afflicted individuals. One such proposed mechanism involves the Protein Kinase C (PKC) family members PKC and PKC{beta}, which have been linked to diabetes-induced tissue damage to organs including the kidneys. To evaluate the therapeutic potential of dual inhibition of PKC and PKC{beta} in the context of T2D, we have evaluated a potent and orally bioavailable inhibitor, herein referred to as Cmpd 1, in the ZSF1 rat model of leptin-receptor deficiency, obesity-driven T2D. Therapeutic dosing of Cmpd 1 virtually halted renal function decline but did so indirectly by blunting the hyperphagia response of these animals. Beyond this clear but indirect effect, Cmpd 1 had direct and prominent effects on body weight and in liver and inguinal white adipose tissue (iWAT) when administered to ZSF1 obese rats.

pharmacology and toxicology↗

bioRxiv2020

Passive motor learning: Oculomotor adaptation in the absence of feedback on behavioral errors

Motor adaptation is commonly thought to be a trial-and-error process in which accuracy of movement improves with repetition of behavior. We challenged this view by testing whether erroneous movements are necessary for motor adaptation. In the eye movement system, the association between motor command and errors can be disentangled, since errors in the predicted stimulus trajectory can be perceived even without movements. We modified a smooth pursuit eye movement adaptation paradigm in which monkeys learn to make an eye movement that predicts an upcoming change in target direction. We trained monkeys to fixate on a target while covertly, an additional target initially moved in one direction and then changed direction after 250 ms. Monkeys showed a learned response to infrequent probe trials in which they were instructed to follow the moving target. Further experiments confirmed that probing learning or residual eye movement during fixation did not drive learning. These results show that movement is not necessary for motor adaptation and provide an animal model for studying how passive learning is implemented. The standard model assumes that the interaction between movement and error signals in the cerebellum underlies adaptive learning. Our results indicate that either sensory inputs are sufficient for driving learning in the cerebellum or that learning is implemented partly outside the cerebellum.

neuroscience↗

bioRxiv2019

Inhibition of ATR Reverses a Mitochondrial Respiratory Insufficiency

Diseases that affect the mitochondrial electron transport chain (ETC) often manifest as threshold effect disorders, meaning patients only become symptomatic once a certain level of ETC dysfunction is reached. Multiple processes work to control proximity to the critical ETC threshold and as a consequence there can be significant variability in disease presentation among patients. Identification of such control processes remains an ongoing goal. Checkpoint signaling comprises a collection of alert mechanisms activated in cells in response to nuclear DNA damage. Well-defined hierarchies of proteins are involved in both sensing and signaling DNA damage, with ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) acting as pivotal signaling kinases. In the nematode C. elegans, severe reduction of mitochondrial ETC activity shortens life, as in humans, but mild reduction extends life as a consequence of survival strategies that are invoked under these circumstances. Here we show that removal of ATL-1, the worm ortholog of ATR, unexpectedly lessens the severity of ETC dysfunction, but removal of ATM does not. Multiple genetic and biochemical tests show no evidence for increased mutation or DNA breakage in animals exposed to ETC disruption. Instead, we find that reduced ETC function alters nucleotide ratios within both the ribo- and deoxyribo-nucleotide pools, and causes stalling of RNA polymerase, which is also known to activate ATR. Unexpectedly, atl-1 mutants confronted with mitochondrial ETC disruption maintain normal levels of oxygen consumption and have an increased abundance of translating ribosomes. This suggests checkpoint signaling by ATL-1 normally dampens cytoplasmic translation. Taken together, our data suggests a model whereby ETC insufficiency in C. elegans results in nucleotide imbalances leading to stalling of RNA polymerase, activation of ATL-1, dampening of global translation and magnification of ETC dysfunction. Loss of ATL-1 effectively reverses the severity of ETC disruption so that animals become phenotypically closer to wild type.

pathology↗