Biology subjects

Millan, E. Z.

Publications and source records attributed to Millan, E. Z..

4 recordsLinked to original sources

bioRxiv2024

FGF21 Analogue PF-05231023 on Alcohol Consumption and Neuronal Activity in the Nucleus Accumbens

Fibroblast growth factor 21 (FGF21) is a liver-derived hormone known to suppress alcohol consumption in mice and non-human primates. However, the role of FGF21 in modulating environmental and behavioural factors driving alcohol consumption--such as cue-driven responses and effortful actions to obtain alcohol--and its effects on neural activity related to consumption, remain unclear. Here, we evaluated the impact of PF-05231023, a long-acting FGF21 analogue, across multiple dimensions of alcohol consumption and motivation. PF-05231023 reduced alcohol intake and preference in a dose-and sex-specific manner; diminished approach behaviours following an alcohol but not sucrose cue; and decreased lever-pressing under a progressive-ratio schedule, both alone and when combined with the GLP-1 agonist Exendin-4. Additionally, PF-05231023 altered the microstructure of alcohol consumption by shortening drinking bouts and increased the recruitment of nucleus accumbens (Acb) neurons associated with bout termination. These findings demonstrate that PF-05231023 broadly suppresses alcohol-motivated behaviours and that targeting FGF21 signaling in combination with GLP-1 agonists may enhance therapeutic efficacy. Mechanistically, the observed reductions in alcohol consumption following PF-05231023 appear to involve diminished alcohol palatability and modulation of neuronal activity from distinct subsets of Acb neurons.

neuroscience↗

bioRxiv2021

A corticothalamic circuit trades off speed for safety during decision-making under motivational conflict

Decisions to act while pursuing goals in the presence of danger must be made quickly but safely. Premature decisions risk injury or death whereas postponing decisions risk goal loss. Here we show how mice resolve these competing demands. Using microstructural behavioral analyses, we identified the spatiotemporal dynamics of approach-avoidance decisions under motivational conflict. Then we used cognitive modelling to show that these dynamics reflect the speeded decision-making mechanisms used by humans and non-human primates, with mice trading off decision speed for safety of choice when danger loomed. Using calcium imaging and functional circuit analyses, we show that this speed-safety trade off occurs because increases in paraventricular thalamus (PVT) activity increase decision caution, thereby increasing approach-avoid decision times in the presence of danger. Our findings demonstrate that a discrete brain circuit involving the PVT and its prefrontal cortical input dynamically adjusts decision caution during motivational conflict, trading off decision speed for decision safety when danger is close. They identify the corticothalamic pathway as central to cognitive control during decision-making under conflict.

neuroscience↗

bioRxiv2021

Rapid appetitive transitions are sculpted by amygdala to accumbens pathways

Foraging, pursuit, and predation rapidly transition into behavioral quiescence during reward capture and consumption. While appetitive-consummatory dissociations are embedded at both psychological and neural levels, the mechanisms controlling switches or transitions between appetitive seeking and consummatory behaviors remain poorly understood. Here we identify the BLA[->]AcbSh pathway as critical to these transitions by showing that this pathway inhibits the appetitive seeking response in the presence of consummatory demands. Using an appetitive cue-discrimination task in male rats, we show that reward delivery is a significant driver of seeking inhibition and that a BLA[->]AcbSh pathway mediates this inhibition. This role in suppressing seeking responses during periods of consumption was not due to a general suppression of behavior because responding to other cues during the same test was unaffected. Moreover, it was specific to the BLA[->]AcbSh pathway, because the contribution of the BLA[->]AcbC pathway to appetitive switching was distinct and modest. State-dependent silencing of BLA[->]AcbSh revealed that the modulation of seeking before and after reward delivery are co-dependent. Finally, we found that BLA terminals in AcbSh have functional connectivity to LH-projecting AcbSh neurons, thereby identifying a BLA[->]AcbSh[->]LH pathway as a putative route for the rapid regulation of appetitive behaviors. Taken together, these findings suggest that the BLA[->]AcbSh pathway is a core component of an appetitive switching system, recruited under conditions requiring rapid or dynamic shifts in appetitive behavior, and that this pathway enables these shifts by actively inhibiting seeking. Significance statementForaging, pursuit, and predation quickly transition into behavioral quiescence during reward capture and consumption. These transitions are critical for flexible and responsive sequences of behavior. Here we show that behavioral transitions are actively controlled at the limbic-striatal interface. We identify reward receipt as a proximal trigger for transition between reward seeking and taking, we identify active inhibition as the functional operation of this transition, and we identify the basolateral amygdala[->]accumbens shell pathway as critical to this functional operation.

neuroscience↗

bioRxiv2017

Basolateral amygdala glutamatergic neurons maintain aversive emotional salience

Basolateral amygdala (BLA) glutamatergic neurons serve a well-accepted role in fear conditioning and fear extinction. However, the specific learning processes related to their activity at different times during learning remain poorly understood. We addressed this using behavioral tasks isolating distinct aspects of fear learning in rats. We show that brief optogenetic inhibition of BLA glutamatergic neurons around moments of aversive reinforcement or non-reinforcement causes reductions in the salience of conditioned stimuli, rendering these stimuli less able to be learned about and less able to control fear or safety behaviours. This salience reduction was stimulus-specific, long-lasting, and specific to aversive emotional states - precisely the goals of therapeutic interventions in human anxiety disorders. Our findings identify a core learning process disrupted by brief BLA optogenetic inhibition. They show that a primary function of BLA glutamatergic neurons is to maintain the salience of conditioned stimuli. This is a necessary precursor for these stimuli to gain and maintain control over fear and safety behavior.\n\nSignificance statementThe amygdala is essential for learning to fear and learning to reduce fear. However, the specific roles served by activity of different amygdala neurons at different times during learning is poorly understood. We used behavioral tasks isolating distinct aspects of learning in rats to show that brief optogenetic inhibition of BLA glutamatergic neurons around moments of reinforcement or non-reinforcement disrupts maintenance of conditioned stimulus (CS) salience. This causes a stimulus-specific, long-lasting, and aversive emotion specific deficit in the ability of the CS to be learned about or control fear responses. These consequences are the precisely goals of therapeutic interventions in human anxiety disorders. Our findings identify a core learning process disrupted by brief BLA optogenetic inhibition.

neuroscience↗