Biology subjects

Linares-Garcia, I.

Publications and source records attributed to Linares-Garcia, I..

6 recordsLinked to original sources

bioRxiv2026

Learning shapes neural codes for sensory-motor integration in the tail of the striatum

Separating meaningful sensory stimuli from irrelevant ones requires learning sensorimotor associations, but how sensory-linked striatal circuits acquire and maintain these associations is unclear. We longitudinally imaged direct- and indirect-pathway (D1 and A2a) spiny projection neurons (SPNs) in the tail of the striatum (TS) as mice learned to push or pull a joystick in response to auditory cues in either a stimulus-response association (go/omit) task or a two-alternative forced choice (2AFC) task. Learning in both tasks increased the fraction and strength of task-modulated TS SPNs across the sound, action, and reward epochs, yet individual neuron selectivity often switched over days between behavioral epochs. In spite of individual neuron variability, population activity of direct and indirect pathways became aligned with characteristic behavioral features during learning: D1-SPNs dominated the action category, A2a-SPNs were biased toward the mixed category (multiple epochs), and both SPN types showed sound category specificity that depended on the sound-action association. Trial-wise modeling revealed a reweighting of behavioral predictors within the action window, with reward gaining and movement losing predictive weight. Learning the two-choice task led to a higher prevalence of association-preferring neurons and better behavioral decoding within the sound window than in the action/reward window, reflecting a task-dependent prioritization of sensory information. Association-preferring neurons also showed a stable local distance-similarity relationship, with nearby neurons more similar than distant neurons across learning. Together, our results support a population mechanism in TS during learning in which neurons from both direct and indirect pathways are recruited and take on distinct behavioral roles that vary with performance and task complexity.

neuroscience↗

bioRxiv2025

Neuropathic pain drives time-dependent reorganization of corticostriatal circuits

Chronic pain fundamentally alters sensorimotor integration and motivated behaviors, yet the neural mechanisms underlying this transition remain poorly understood. The striatum, composed of dopamine receptor type 1 (D1)- and type 2 (D2)-expressing spiny projection neurons (SPN), integrates cortical sensory and motor inputs to coordinate movement and motivation, making it a critical candidate for mediating pain-induced behavioral adaptations. Although spinal and cortical pain circuits are well-characterized in limited phases of pain, how corticostriatal pathways and distinct striatal cell populations contribute to the transition from acute to chronic pain states remains unclear. Here we show that neuropathic pain, after spared nerve injury in mice, produces temporally distinct, cell-type-specific changes in striatal SPN activity and corticostriatal plasticity that evolve across acute to chronic pain phases. D1 SPNs exhibit smaller amplitude and slower calcium signals during acute pain stages that persist through early chronic phases, while D2 SPNs show delayed response timing during later chronic stages, but also stimulus-specific alterations in neural activity throughout acute and chronic pain states. Critically, primary somatosensory cortex inputs to D2 SPNs develop depressing synapses specifically during intermediate chronic pain phases ([~]25 days post-injury) that disappear during more severe chronic stages (>3 months), suggesting a failed compensatory mechanism. These findings reveal that striatal circuits undergo dynamic, time-dependent reorganization after peripheral injury, with D1 and D2 pathways contributing distinct temporal signatures to pain-related behavior. The identification of critical windows of striatal plasticity provides new targets for therapeutic interventions that could prevent or reverse chronic pain states by modulating specific corticostriatal circuits during vulnerable transition periods.

neuroscience↗

bioRxiv2025

An Open-Source Joystick Platform for Investigating Forelimb Motor Control, Auditory-Motor Integration, and Value-Based Decision-Making in Head-Fixed Mice

Investigation of neural processes underlying motor control requires behavioral readouts that capture the richness of actions, including both categorical (choice-based) information and motor execution (kinematics). We present an open-source platform for behavioral training of head-fixed mice that combines a stationary or retractable forelimb-based joystick, sound-presentation system, capacitive lick sensor, and water reward dispenser. The setup allows for the creation of multiple behavioral paradigms, two of which are highlighted here: a two-alternative forced-choice auditory-motor discrimination paradigm, and a two-armed bandit value-based decision-making task. In the auditory-motor paradigm, mice learn to report high or low frequency tones by pushing or pulling the joystick. In the value-based paradigm, mice learn to push or pull the joystick based on the history of rewarded trials. In addition to reporting categorical choices, this setup provides a rich dataset of motor parameters that reflect components of the underlying learning and decision processes in both of these tasks. These kinematic parameters (including joystick speed and displacement, Frechet similarity of trajectories, tortuosity, angular standard deviation, and movement vigor) provide key additional insights into the motor execution of choices that are not as readily assessed in other paradigms. The systems flexibility of task design, joystick readout, and ease of construction represent an advance compared to currently available manipulandum tasks in mice. We provide detailed schematics for constructing the setup and protocols for behavioral training using both paradigms, with the hope that this open-source resource is readily adopted by neuroscientists interested in mechanisms of sensorimotor integration, motor control, and choice behavior. Significance StatementBehavioral paradigms for experiments in head-restrained mice are important for investigating the relationship between neural activity and behavior. However, behavioral setups are often constrained by high cost, design complexity, and implementation challenges. Here, we present an open-source platform for behavioral training of head-fixed mice using a joystick manipulandum. The setup allows for the creation of multiple behavioral paradigms, including an auditory-motor discrimination paradigm, and a value-based decision-making task. We include detailed instructions for construction and implementation of the entire open-source behavioral platform.

neuroscience↗

bioRxiv2024

Role of Posterior Medial Thalamus in the Modulation of Striatal Circuitry and Choice Behavior

The posterior medial (POm) thalamus is heavily interconnected with sensory and motor circuitry and is likely involved in behavioral modulation and sensorimotor integration. POm provides axonal projections to the dorsal striatum, a hotspot of sensorimotor processing, yet the role of POm-striatal projections has remained undetermined. Using optogenetics with slice electrophysiology, we found that POm provides robust synaptic input to direct and indirect pathway striatal spiny projection neurons (D1- and D2-SPNs, respectively) and parvalbumin-expressing fast spiking interneurons (PVs). During the performance of a whisker-based tactile discrimination task, POm-striatal projections displayed learning-related activation correlating with anticipatory, but not reward-related, pupil dilation. Inhibition of POm-striatal axons across learning caused slower reaction times and an increase in the number of training sessions for expert performance. Our data indicate that POm-striatal inputs provide a behaviorally relevant arousal-related signal, which may prime striatal circuitry for efficient integration of subsequent choice-related inputs.

neuroscience↗

bioRxiv2023

A paradigm for ethanol consumption in head-fixed mice during prefrontal cortical two-photon calcium imaging

The prefrontal cortex (PFC) is a hub for higher-level cognitive behaviors and is a key target for neuroadaptations in alcohol use disorders. Preclinical models of ethanol consumption are instrumental for understanding how acute and repeated drinking affects PFC structure and function. Recent advances in genetically encoded sensors of neuronal activity and neuromodulator release combined with functional microscopy (multiphoton and one-photon widefield imaging) allow multimodal in-vivo PFC recordings at subcellular and cellular scales. While these methods could enable a deeper understanding of the relationship between alcohol and PFC function/dysfunction, they require animals to be head-fixed. Here, we present a method in mice for binge-like ethanol consumption during head-fixation. Male and female mice were first acclimated to ethanol by providing home cage access to 20% ethanol (v/v) for 4 or 8 days. After home cage drinking, mice consumed ethanol from a lick spout during head-fixation. We used two-photon calcium imaging during the head-fixed drinking paradigm to record from a large population of PFC neurons (>1000) to explore how acute ethanol affects their activity. Drinking modulated activity rates in a subset of neurons on slow (minutes) and fast (seconds) time scales but the majority of neurons were unaffected. Moreover, ethanol intake did not significantly affect network level interactions in the PFC as assessed through inter-neuronal pairwise correlations. By establishing a method for binge-like drinking in head-fixed mice, we lay the groundwork for leveraging advanced microscopy technologies to study alcohol-induced neuroadaptations in PFC and other brain circuits. HighlightsO_LIC57BL/6J mice voluntarily consume ethanol to binge-like levels during head-fixation, with females consuming more ethanol than males. C_LIO_LIMice show differences in frontloading and licking behavior for head-fixed ethanol and sucrose consumption. C_LIO_LIHead-fixed paradigm enables two-photon calcium imaging in the anterior cingulate cortex subdivision of the prefrontal cortex. C_LIO_LIAcute ethanol increases and decreases single neuron activity at fast (seconds) and slow (minutes) time scales but does not alter pairwise correlations between neurons. C_LI

neuroscience↗

bioRxiv2021

Voluntary alcohol consumption disrupts coupling of prefrontal cortical activity to arousal

Alcohol use disorder (AUD) exacts a major personal, societal, and economic toll. Top-down control from the prefrontal cortex (PFC), a critical hub for decision making, executive, and other cognitive functions, is key for the regulation of alcohol consumption. Arousal exerts profound effects on cortical processing, allowing it to potentially modulate PFC functions relevant for alcohol consumption and AUD. Despite this, it is unclear whether and how arousal-mediated modulation of PFC circuits relates to voluntary alcohol drinking behaviors. Two-photon microscopy is ideally suited for dissecting the neural circuit mechanisms underlying the effect of alcohol on intact circuits in behaving animals. We addressed a major limitation of this technology by developing a novel behavioral paradigm for voluntary drinking in head-fixed mice. We recorded responses of layer 2/3 excitatory neurons in the anterior cingulate cortex (ACC) subdivision of the PFC as mice voluntarily consumed ethanol, along with video recording of the pupil to track momentary fluctuations in arousal. Ethanol consumption bidirectionally modified the activity of subsets of ACC neurons, both at slow (minutes) and fast (sub-second) time scales. Remarkably, we found that the coupling of arousal to ACC activity before drinking was associated with subsequent ethanol engagement behavior. In turn, ethanol consumption modulated neuronal-arousal coupling. Together, our results suggest neuronal-arousal coupling as a key biomarker for alcohol drinking and lays the groundwork for future studies to dissect the therapeutic potential of this process for AUD and other substance use disorders.

neuroscience↗