Biology subjects

Llorach, P.

Publications and source records attributed to Llorach, P..

4 recordsLinked to original sources

bioRxiv2026

Brain-wide Activity Mapping Reveals the Somatosensory Cortex as a Sex-Specific Regulator of High-Fat Diet Intake

High-fat diet (HFD) consumption engages reward circuitry and promotes neuroadaptations that contribute to overeating and obesity. While mesolimbic dopamine pathways are central to hedonic feeding models, the contribution of sensory cortical systems remains poorly understood. Here, we performed whole-brain activity mapping using Targeted Recombination in Active Populations (TRAP) and network analysis to define the distributed neural consequences of short-term HFD exposure in male and female mice. HFD increased caloric intake in both sexes, with females consuming significantly more than males. Brain-wide analysis revealed striking sex-specific adaptations: HFD selectively increased isocortical activity in males, with the somatosensory cortex (SS) emerging as the most prominently modulated region. SS activity negatively correlated with HFD intake, primarily in males. Network analysis using the SMARTTR pipeline demonstrated that HFD reorganized network activity in a sex-dependent manner, biasing male networks toward associative cortical-thalamic hubs, whereas female networks preferentially recruited subcortical and brainstem structures. To determine causality, we bidirectionally manipulated SS pyramidal neurons using chemogenetics during limited-access HFD exposure. Inhibition of the SS increased HFD intake in males, whereas activation reduced cumulative intake in females, without affecting locomotion. These findings establish the SS as a sex-specific regulator of palatable food consumption and demonstrate that similar behavioral outcomes emerge from distinct circuit architectures across sexes. Collectively, this study expands prevailing reward-centric models of hedonic feeding by identifying sensory cortical control as a critical component of diet-induced neuroadaptations, with important implications for sex-specific therapeutic strategies targeting overeating and obesity.

neuroscience↗

bioRxiv2025

Divergent Roles of Nucleus Accumbens D1- and D2-MSNs in Regulating Hedonic Feeding

The nucleus accumbens (NAc) is a critical node in the neural circuitry underlying reward and motivated behavior, including hedonic feeding, and its dysfunction is implicated in maladaptive behaviors in numerous psychiatric disorders. Medium spiny neurons (MSNs) in the NAc are predominantly categorized into dopamine 1 receptor-expressing (D1-MSNs) and dopamine 2 receptor-expressing (D2-MSNs) subtypes, which are thought to exert distinct and sometimes opposing roles in reward-related processes. Here, we used optogenetic, chemogenetic, and fiber photometry approaches in Cre-driver mouse lines to dissect the causal contributions of D1- and D2-MSNs to the consumption of a high-fat diet in sated animals. Activation of D1-MSNs via optogenetics or DREADDs significantly suppressed high-fat intake, whereas inhibition of these neurons increased consumption only in male but not female mice. Conversely, activation of D2-MSNs enhanced high-fat intake only in females, while their inhibition reduced intake in both sexes. Fiber photometry revealed dynamic shifts in D2-MSN activity over repeated high-fat exposures, with increasing activity correlating with escalating intake of high-fat diet only in female mice. These results highlight opposing contributions of D1- and D2-MSN populations in regulating hedonic feeding and support a model in which salience and consumption are modulated by NAc MSN subtype-specific activity in a sex-specific manner. Understanding this circuitry has implications for the development of tailored treatment strategies for obesity and other disorders of compulsive consumption. Significance StatementObesity and metabolic disorders are partly driven by dysregulated motivation for palatable foods, yet the neural circuits underlying hedonic feeding are not fully understood. This study shows that nucleus accumbens medium spiny neurons have differential, sex-specific roles in high-fat intake: D1-MSN activity suppresses intake in male mice, while D2-MSNs promote consumption in female mice. Using chemogenetics, optogenetics, and fiber photometry, we establish a causal link between MSN activity and hedonic feeding. These findings expand previous models of reward processing and highlight the experience and sex-dependent roles of MSN subtypes. By defining cell-type-specific contributions to non-homeostatic eating, this work offers key insight into the neural basis of hedonic intake and informs strategies for targeted intervention in obesity and related conditions.

neuroscience↗

bioRxiv2024

5-HT2C receptors in the nucleus accumbens constrain the rewarding effects of MDMA

MDMA is a promising adjunct to psychotherapy and has well-known abuse liability, although less than other amphetamine analogs. While the reinforcing dopamine (DA)-releasing properties of MDMA are on par with methamphetamine (METH), MDMA is a far more potent serotonin (5-HT) releaser, via the 5-HT transporter (SERT). MDMA-mediated 5-HT release in a major reward center, the nucleus accumbens (NAc), drives prosocial behaviors via 5-HT1BR activation. We hypothesized that this prosocial mechanism contributes to the reduced reinforcing properties of MDMA compared to METH and used a platform of assays to predict the balance of prosocial and abuse-linked effects of (R)-MDMA, a novel entactogen in clinical development. NAc DA release, measured by GRAB-DA photometry in vivo, increased in proportion to MDMA (7.5 and 15 mg/kg, i.p.) and METH (2 mg/kg i.p.)-conditioned place preference (CPP). Using conditional knockouts (cKOs) for DAT and SERT, microdialysis, and photometry, we found that MDMA-released 5-HT limited MDMA-released DA through actions in the NAc, rather than at ventral tegmental area DAergic cell bodies. SERT cKO reduced the MDMA dose required for CPP three-fold. This enhanced MDMA-CPP and increased DA release were replicated by intra-NAc infusion of either a 5-HT reuptake inhibitor (escitalopram) to prevent MDMA interaction with SERT, or a 5-HT2CR antagonist (SB242084), but not by the 5-HT1BR antagonist NAS-181. These data support separate mechanisms for the low abuse potential versus prosocial effect of MDMA. Using this platform of assays, (R)-MDMA is predicted to have prosocial effects and low abuse potential.

neuroscience↗

bioRxiv2024

Opioid receptor expressing neurons of the central amygdala gate behavioral effects of ketamine in mice

Ketamine has anesthetic, analgesic, and antidepressant properties which may involve multiple neuromodulatory systems. In humans, the opioid receptor (OR) antagonist naltrexone blocks the antidepressant effect of ketamine. It is unclear whether naltrexone blocks a direct effect of ketamine at ORs, or whether normal functioning of the OR system is required to realize the full antidepressant effects of treatment. In mice, the effect of ketamine on locomotion, but not analgesia or the forced swim test, was sensitive to naltrexone and was therefore used as a behavioral readout to localize the effect of naltrexone in the brain. We performed whole-brain imaging of cFos expression in ketamine-treated mice, pretreated with naltrexone or vehicle, and identified the central amygdala (CeA) as the area with greatest difference in cFos intensity. CeA neurons expressing both {micro}OR (MOR) and PKC{delta} were strongly activated by naltrexone but not ketamine, and selectively interrupting MOR function in the CeA either pharmacologically or genetically blocked the locomotor effects of ketamine. These data suggest that MORs expressed in CeA neurons gate behavioral effects of ketamine but are not direct targets of ketamine.

neuroscience↗