Biology subjects

Castro-Alamancos, M. A.

Publications and source records attributed to Castro-Alamancos, M. A..

5 recordsLinked to original sources

bioRxiv2025

Subthalamic nucleus controls cautious action timing under threat

Adaptive goal-directed actions performed under the threat of punishment introduce a demand for caution, often expressed as delayed response timing that balances urgency against error risk by allowing more time for cognitive evaluation. Although this form of temporal regulation is essential for survival, its underlying neural mechanisms remain poorly understood. We show that glutamatergic neurons in the subthalamic nucleus (STN) regulate the timing of cued actions to avoid harm. Optogenetic activation of the STN, or its projections to the midbrain but not the globus pallidus, modulates action timing in a frequency-dependent manner, accelerating initiation to the extent that animals can no longer respond cautiously, defer actions, or stop initiated actions. These results show that the STN shapes goal-directed behavior by gating action-initiation timing, establishing its midbrain projections as a key circuit for balancing urgency and caution under threat. Significance statementThis work shows that activity in the subthalamic nucleus (STN) helps set the timing of actions triggered by warning cues. By activating STN neurons and their projections to the midbrain, we found that stimulation made animals respond faster, and high-frequency activation eliminated their ability to delay actions when caution was required or to withhold actions that would otherwise be punished. These findings highlight a key brain pathway that governs when actions are initiated, a function that is often disrupted in neurological and psychiatric disorders.

neuroscience↗

bioRxiv2025

Encoding without generation in the medial prefrontal cortex during cautious goal-directed actions

Adaptive behavior under threat requires deciding when to act and when to withhold action to avoid harm, often under conditions where movement, arousal, and task demand covary. Medial prefrontal cortex (mPFC) activity is widely associated with such control, yet it remains unclear whether this activity reflects causal action generation or broader evaluative processes shaped by behavioral state. Here, we combined fiber photometry, single-cell calcium imaging, mixed-effects modeling, and optogenetic inhibition to examine how GABAergic neurons in mouse mPFC represent cues, actions, and outcomes during a series of learned avoidance tasks of increasing complexity that promote cautious responding. By explicitly controlling for baseline activity and movement, we show that much apparent task-related activity in mPFC reflects movement and cue-evoked signals that are also present in a control cortical region, the visual cortex. mPFC GABAergic neurons showed little encoding of simple avoidance contingencies but broadly encoded punished outcomes. A small subset of neurons with strong movement sensitivity encoded more demanding avoidance contingencies requiring selection between action generation and deferment. For equivalent avoidance actions, distinct neuronal populations preferentially encoded either cue onset or the action. Despite this encoding, optogenetic inhibition of mPFC had minimal effects on the learning or performance of the different contingencies. These findings reveal a dissociation between neural encoding and causal necessity, indicating that mPFC GABAergic activity primarily reflects evaluative and contextual aspects of cautious avoidance behavior rather than direct control of action execution. Significance statementAvoiding danger often requires deciding when to act and when to hold back. The dorsomedial prefrontal cortex (mPFC) is widely assumed to support this control, yet the contributions of its neurons have remained unclear. Using neural population and single-neuron recordings together with targeted inhibition in mice performing learned threat-guided tasks, we show that GABAergic mPFC neurons are activated by cues, actions, and outcomes, but are not required for executing the behavior itself. These findings suggest that the mPFC primarily evaluates and contextualizes threat-motivated actions rather than generating them, highlighting a common mismatch between neural encoding and causal necessity.

neuroscience↗

bioRxiv2025

A Forebrain Hub for Cautious Actions via the Midbrain

Adaptive goal-directed behavior requires dynamic coordination of movement, motivation, and environmental cues. Among these, cautious actions, where animals adjust their behavior in anticipation of predictable threats, are essential for survival. Yet, their underlying neural mechanisms remain less well understood than those of appetitive behaviors, where caution plays little role. Using calcium imaging in freely moving mice we show that glutamatergic neurons in the subthalamic nucleus (STN) are robustly engaged by contraversive movement during cue-evoked avoidance and exploratory behavior. Model-based analyses controlling for movement and other covariates revealed that STN neurons additionally encode salient sensory cues, punished errors, and especially cautious responding, where their activity anticipates avoidance actions. Targeted lesions and optogenetic manipulations reveal that STN projections to the midbrain are necessary for executing cued avoidance. These findings identify a critical role for the STN in orchestrating adaptive goal-directed behavior by integrating sensory, motor, and punitive signals to guide timely, cautious actions via its midbrain projections. Significance statementThis study provides new insights into the neural pathways that mediate adaptive goal-directed behaviors in response to environmental cues, identifying a critical role for glutamatergic projections from the subthalamic nucleus (STN) to the midbrain. We show that STN activation encodes caution and is essential for cued goal-directed actions. These findings deepen our understanding of the circuits involved in cued goal-directed adaptive behaviors used to cope with contextual challenges, which are often altered by brain disorders.

neuroscience↗

bioRxiv2024

Role of the nucleus accumbens in signaled avoidance actions

Animals, humans included, navigate their environments guided by sensory cues, responding adaptively to potential dangers and rewards. Avoidance behaviors serve as adaptive strategies in the face of signaled threats, but the neural mechanisms orchestrating these behaviors remain elusive. Current circuit models of avoidance behaviors indicate that the nucleus accumbens (NAc) in the ventral striatum plays a key role in signaled avoidance behaviors, but the nature of this engagement is unclear. Evolving perspectives propose the NAc as a pivotal hub for action selection, integrating cognitive and affective information to heighten the efficiency of both appetitive and aversive motivated behaviors. To unravel the engagement of the NAc during active and passive avoidance, we used calcium imaging fiber photometry and single-unit recordings to examine NAc GABAergic neuron activity in freely moving mice performing avoidance behaviors. We then probed the functional significance of NAc neurons using optogenetics, and genetically targeted or electrolytic lesions. We found that NAc neurons code contraversive orienting movements and avoidance actions. Intriguingly, specific optogenetic patterns intended to excite NAc GABAergic neurons resulted in local somatic inhibition through GABAergic synaptic collaterals. Nevertheless, these patterns directly excited NAc GABAergic output axons, which in turn inhibited their targets, disrupting active avoidance behavior. Thus, this disruption stemmed from abnormal alterations in the activity of downstream midbrain areas crucial for the behavior. In contrast, direct optogenetic inhibition or lesions of NAc neurons did not impair active or passive avoidance behaviors, challenging the notion of their purported pivotal role in adaptive avoidance. The findings emphasize that NAc is not required for avoidance behaviors, but disruptions in NAc output during pathological states can impair these behaviors.

neuroscience↗

bioRxiv2023

Zona incerta distributes a broad movement signal that modulates behavior

The zona incerta is a subthalamic nucleus made up mostly of GABAergic neurons. It has wide- ranging inputs and outputs and is believed to have many integrative functions that link sensory stimuli with motor responses to guide behavior. However, its role is not well established perhaps because few studies have measured the activity of zona incerta neurons in behaving animals under different conditions. To record the activity of zona incerta neurons during exploratory and cue-driven goal-directed behaviors, we used electrophysiology in head-fixed mice moving on a spherical treadmill and fiber photometry in freely moving mice. We found two groups of neurons based on their sensitivity to movement, with a minority of neurons responding to whisker stimuli. Furthermore, zona incerta GABAergic neurons robustly code the occurrence of exploratory and goal-directed movements, but not their direction. To understand the function of these activations, we performed genetically targeted lesions and optogenetic manipulations of zona incerta GABAergic neurons during exploratory and goal-directed behaviors. The results showed that the zona incerta has a role in modulating the movement associated with these behaviors, but this has little impact on overall performance. Zona incerta neurons distribute a broad corollary signal of movement occurrence to their diverse projection sites, which regulates behavior.

neuroscience↗