Biology subjects

Kuchibhotla, K. V.

Publications and source records attributed to Kuchibhotla, K. V..

5 recordsLinked to original sources

bioRxiv2025

Revealing hidden knowledge in amnestic mice

Alzheimers disease (AD) is a form of dementia in which memory and cognitive decline is thought to arise from underlying neurodegeneration. These cognitive impairments, however, are transient when they first appear and can fluctuate across disease progression. Here, we investigate the neural mechanisms underlying fluctuations of performance in amnestic mice. We trained APP/PS1+ mice on an auditory go/no-go task that dissociated learning of task contingencies (knowledge) from its more variable expression under reinforcement (performance). APP/PS1+ exhibited significant performance deficits compared to control mice. Using large-scale two-photon imaging of 6,216 excitatory neurons in 8 mice, we found that auditory cortical networks were more suppressed, less selective to the sensory cues, and exhibited aberrant higher-order encoding of reward prediction compared to control mice. A small sub-population of neurons, however, displayed the opposite phenotype, reflecting a potential compensatory mechanism. Volumetric analysis demonstrated that deficits were concentrated near A{beta} plaques. Strikingly, we found that these cortical deficits were reversed almost instantaneously on probe (non-reinforced) trials when APP/PS1+ performed as well as control mice, providing neural evidence for intact stimulus-action knowledge despite variable ongoing performance. A biologically-plausible reinforcement learning model recapitulated these results and showed that synaptic weights from sensory-to-decision neurons were preserved (i.e. intact stimulus-action knowledge) despite poor performance that was due to inadequate contextual scaling (i.e. impaired performance). Our results suggest that the amnestic phenotype is transient, contextual, and endogenously reversible, with the underlying neural circuits retaining the underlying stimulus-action associations. Thus, memory deficits commonly observed in amnestic mouse models, and potentially at early stages of dementia in humans, relate more to contextual drivers of performance rather than degeneration of the underlying memory traces.

neuroscience↗

bioRxiv2023

Revealing abrupt transitions from goal-directed to habitual behavior

A fundamental tenet of animal behavior is that decision-making involves multiple controllers. Initially, behavior is goal-directed, driven by desired outcomes, shifting later to habitual control, where cues trigger actions independent of motivational state. Clark Hulls question from 1943 still resonates today: "Is this transition abrupt, or is it gradual and progressive?"1 Despite a century-long belief in gradual transitions, this question remains unanswered2,3 as current methods cannot disambiguate goal-directed versus habitual control in real-time. Here, we introduce a novel volitional engagement approach, motivating animals by palatability rather than biological need. Offering less palatable water in the home cage4,5 reduced motivation to work for plain water in an auditory discrimination task when compared to water-restricted animals. Using quantitative behavior and computational modeling6, we found that palatability-driven animals learned to discriminate as quickly as water-restricted animals but exhibited state-like fluctuations when responding to the reward-predicting cue--reflecting goal-directed behavior. These fluctuations spontaneously and abruptly ceased after thousands of trials, with animals now always responding to the reward-predicting cue. In line with habitual control, post-transition behavior displayed motor automaticity, decreased error sensitivity (assessed via pupillary responses), and insensitivity to outcome devaluation. Bilateral lesions of the habit-related dorsolateral striatum7 blocked transitions to habitual behavior. Thus, volitional engagement reveals spontaneous and abrupt transitions from goal-directed to habitual behavior, suggesting the involvement of a higher-level process that arbitrates between the two.

neuroscience↗

bioRxiv2023

Spatially clustered neurons encode vocalization categories in the bat midbrain

Rapid categorization of vocalizations enables adaptive behavior across species. While categorical perception is thought to arise in the neocortex, humans and other animals could benefit from functional organization of ethologically-relevant sounds at earlier stages in the auditory hierarchy. Here, we developed two-photon calcium imaging in the awake echolocating bat (Eptesicus fuscus) to study encoding of sound meaning in the Inferior Colliculus, which is as few as two synapses from the inner ear. Echolocating bats produce and interpret frequency sweep-based vocalizations for social communication and navigation. Auditory playback experiments demonstrated that individual neurons responded selectively to social or navigation calls, enabling robust population-level decoding across categories. Strikingly, category-selective neurons formed spatial clusters, independent of tonotopy within the IC. These findings support a revised view of categorical processing in which specified channels for ethologically-relevant sounds are spatially segregated early in the auditory hierarchy, enabling rapid subcortical organization of call meaning.

neuroscience↗

bioRxiv2022

A parallel channel of state-dependent sensory signaling from the cholinergic basal forebrain to the auditory cortex

Cholinergic basal forebrain (CBF) signaling exhibits multiple timescales of activity with classic, slow signals related to brain and behavioral states and faster, phasic signals reflecting behavioral events, including movement and reinforcement. Recent evidence suggests that the CBF may also exhibit fast, sensory-evoked responses. It remains unknown, however, whether such sensory signals target the sensory cortex and how they relate to local functional topography. Moreover, the extent to which fast and slow CBF activity interact has been largely unexplored. Here, we used simultaneous two-channel, two-photon imaging of CBF axons and auditory cortical (AC) neurons to reveal that CBF axons project a robust, non-habituating, and stimulus-specific sensory signal to the AC. Individual axon segments exhibited heterogeneous but stable tuning to auditory stimuli allowing stimulus identity to be decoded from the population. However, CBF axons displayed no tonotopy and their frequency tuning was uncoupled from that of nearby cortical neurons. Chemogenetic suppression revealed the auditory thalamus as a principal source of auditory information to the CBF. Finally, slow fluctuations in cholinergic activity modulated the fast, sensory-evoked signals in the same axons, suggesting that a multiplexed combination of fast and slow signals is projected from the CBF to the AC. Taken together, our work demonstrates a novel, non-canonical function of the CBF as a parallel channel of state-dependent sensory signaling to the sensory cortex that provides repeated representations of a broad range of sound stimuli at all points on the tonotopic map.

neuroscience↗

bioRxiv2018

Dissociating task acquisition from expression during learning reveals latent knowledge

Performance on cognitive tasks during learning is used to measure intelligence, yet it remains controversial since such testing is susceptible to contextual factors. To what extent does performance during learning depend on the testing context, rather than underlying knowledge? We trained mice, rats and ferrets on a range of tasks to examine how testing context impacts the acquisition of knowledge versus its expression. We interleaved reinforced trials with \"probe\" trials in which we omitted reinforcement. Across tasks, each animal species performed remarkably better in probe trials during learning and inter-animal variability was strikingly reduced. Reinforcement feedback is thus critical for learning-related plasticity but, paradoxically, masks the expression of underlying knowledge. We capture these results with a network model in which learning occurs during reinforced trials while context modulates only the read-out parameters. Probing learning by omitting reinforcement thus uncovers latent knowledge and identifies context--not \"smartness\"--as the major source of individual variability.\n\nHIGHLIGHTSO_LIKnowledge acquisition and expression can be segregated by the introduction of non-reinforced probe trials across a variety of animal species and behavioral tasks.\nC_LIO_LIAnimals learn much faster and in a more stereotyped way in non-reinforced probe trials than their performance in the presence of reinforcement suggests.\nC_LIO_LIUnderperformance and variability in performance arise from sensitivity to the behavioral testing context, not acquisition of sensorimotor associations.\nC_LIO_LIA circuit model accounts for context-dependent performance by modulating the integration of sensorimotor associations.\nC_LI\n\neTOCKuchibhotla et al. show the acquisition and expression of knowledge can be behaviorally dissociated in mice, rats, and ferrets across a variety of sensorimotor tasks. Across animals, variability in performance arises from the testing context, not underlying aptitude.

neuroscience↗