Biology subjects

Suvrathan, A.

Publications and source records attributed to Suvrathan, A..

3 recordsLinked to original sources

bioRxiv2024

Deficits in forelimb reach learning in a mouse model of Fragile X syndrome

Fragile X syndrome is a leading cause of intellectual disability and autism spectrum disorder, for which therapies are limited. A mouse model of Fragile X syndrome, the Fmr1 knockout (KO) mouse, has been particularly valuable for interrogating the molecular, cellular, and circuit mechanisms that underlie the neurological deficits seen in this syndrome. Key deficits in Fragile X syndrome include impairments in social behaviors, cognition, and motor learning. Given the difficulties in extrapolating more complex human behaviors to mouse models, simple motor behaviors are a particularly tractable form of learning to study in the mouse. We investigated a form of forelimb reach learning in Fmr1 KO mice, precisely quantifying different parameters of the task using both manual analysis and DeepLabCut-based tracking of reach trajectories. While Fmr1 KO mice show impaired learning overall, our results demonstrated that the presence or absence of a cue that signals reward alleviates some of the deficits. In addition to a single metric of success in learning, we determined the specific parameters of the motor behavior that were responsible for that success or failure. In particular, our results suggested that Fmr1 KO mice showed impaired improvement in the trajectory of the reach, reflected by a greater likelihood of completely missing the target, and in a lower learning index for the optimal reach trajectory. In addition, we fully described the features underlying learning, including categorizing the first attempt during trials, failed reaches where mice make contact with the reward, the number of trials where no attempts were made, as well as how the pattern of these different behaviors varies in Fmr1 KO mice. Our findings provide an essential framework for linking specific behavioral impairments in motor learning to the cellular and circuit mechanisms that support them.

neuroscience↗

bioRxiv2024

Heterogeneity in slow synaptic transmission diversifies Purkinje cell timing

The cerebellum plays an important role in diverse brain functions, ranging from motor learning to cognition. Recent studies have suggested that molecular and cellular heterogeneity within cerebellar lobules contributes to functional differences across the cerebellum. However, the specific relationship between molecular and cellular heterogeneity and diverse functional outputs of different regions of the cerebellum remains unclear. Here, we describe a previously unappreciated form of synaptic heterogeneity at parallel fiber synapses to Purkinje cells. In contrast to uniform fast synaptic transmission, we found that the properties of slow synaptic transmission varied by up to three-fold across different lobules of the mouse cerebellum, resulting in surprising heterogeneity. Depending on the location of a Purkinje cell, the time of peak of slow synaptic currents varied by hundreds of milliseconds. The duration and decay-time of these currents also spanned hundreds of milliseconds, based on lobule. We found that, as a consequence of the heterogeneous synaptic dynamics, the same brief stimulus was transformed into prolonged firing patterns over a range of timescales that depended on Purkinje cell location

neuroscience↗

bioRxiv2022

Experience Adaptively Tunes the Timing Rules for Associative Plasticity

The brain learns about the statistical relationships between events in the world through associative synaptic plasticity, controlled by the timing between neural events. Here, we show that experience can dramatically alter the timing rules governing associative plasticity and learning. In normally reared mice, the timing requirements for short- and long-term associative plasticity at synapses in the oculomotor cerebellum are precisely matched to the 120 ms delay for visual feedback to the circuit about behavioral errors. This specialization of the plasticity rules for the constraints of a particular circuit and learning task is acquired through experience. In dark-reared mice that never experienced visual feedback about oculomotor errors, synapses defaulted to a coincidence-based plasticity rule, with a corresponding delay in the timing of learned eye movements. This temporal metaplasticity persists into adulthood; when mice reared normally from birth were moved to dark housing as adults, the task-specific timing requirements for plasticity and the temporal accuracy of learning were lost and then re-established when visual experience was restored. Computational modeling suggests two general classes of biologically plausible mechanisms, each with multiple possible implementations, that can tune plasticity to distinct features of the statistics of neural activity. Temporal metaplasticity provides a potentially general mechanism for experience-dependent improvement in the way a circuit solves the "temporal credit assignment problem" inherent in most learning tasks, thereby providing a candidate synaptic mechanism for meta-learning.

neuroscience↗