Biology subjects

Papaleo, F.

Publications and source records attributed to Papaleo, F..

6 recordsLinked to original sources

bioRxiv2025

Sex-dependent cortico-amygdala circuits controlling emotion recognition

In social species, the ability to recognize others emotional states is essential for appropriate social interactions, yet it often declines with age and is impaired in various neurodevelopmental and neurodegenerative disorders. While emotion recognition has been characterized in both humans and rodents, the underlying neural circuits and how they vary by sex and age remain poorly understood. Here, we used a negative Emotional state Discrimination Task (EDT) in TRAP2 transgenic mice to map brain regions engaged during negative emotion recognition in young and aged animals. Young male and female mice successfully discriminated emotionally altered conspecifics, recruiting the basolateral amygdala (BLA) and medial orbitofrontal cortex (MO) in a sex-specific manner. Fiber photometry revealed distinct activation dynamics in these regions, and chemogenetic inhibition of bidirectional BLA-MO projections abolished emotion recognition in male but not female mice. Notably, young human participants also showed sex-specific recruitment of BLA and OFC during negative facial emotion recognition. Moreover, aging selectively impaired emotion recognition in male mice, coinciding with reduced BLA activity. Remarkably, chemogenetic activation of BLA in aged male mice rescued this deficit. Together, these findings identify a sex-dependent BLA-MO circuit as a conserved neural substrate for emotion recognition and demonstrate that age-related impairments can be reversed through targeted circuit-level intervention.

neuroscience↗

bioRxiv2024

A novel critic signal in identified midbrain dopaminergic neurons of mice training inoperant tasks

Classically, midbrain dopaminergic neuron activity is triggered by unexpected rewards, then, upon learning, by reward-predictive conditioned stimuli. When expected rewards are withheld, firing is inhibited. This activity occurs too late to directly affect the neuronal circuitry underlying decision-making, inspiring the development of temporal difference (TD) reinforcement learning models. To test for more timely critical feedback during decision-making and learning, we recorded optogenetically identified dopaminergic, putative GABAergic and other neurons of the ventral tegmental area (VTA) and substantia nigra pars compacta in mice training in visual and olfactory discrimination tasks. The mice often adhered to unrewarded and untrained task strategies (e.g., spatial alternation) rather than making random choices. In order to probe for reward/punishment predictive activity, a delay was imposed between nose-poke choices and signals for reward or punishment. As animals performed below criterion levels, dopaminergic and other neurons firing rates signaled correct versus incorrect choices immediately after choices, but prior to the onset of trial outcome signals. Thus, this activity signaled the rewarded rule even as the mice performed other unrewarded strategies. Putative GABAergic neurons fired during nose-poke choices, potentially reducing network activity prior to reward prediction signals. This reward predictive activity could serve as a critic signal expressed immediately after choices are made, priming the network for canonical DA reward/punishment activity, facilitating network functional modifications. This is consistent with a role for dopamine in arbitration between brain modules to choose among diverse strategies during goal-directed behavior. These findings suggest extensions of theoretical formulations interpreting dopaminergic neuronal activity. Significance statementModels of dopaminergic influence on circuit modifications during learning evoke mechanisms dealing with the delay between neural activity leading up to choices, and when the reinforcing outcome actually occurs. Here, as mice trained in sensory discrimination tasks with a delay between behavioral responses and reinforcement signals, they performed several unrewarded behavioral strategies. Simultaneously, dopaminergic nuclei neurons instead reflected the current task rule, predicting whether the choice was correct or not, providing an immediate "critic" signal prior to canonical trial outcome signals. This provides evidence for brain mechanisms to overcome innate or acquired habits to perform behaviors optimizing positive outcomes.

neuroscience↗

bioRxiv2024

Synaptic-dependent developmental dysconnectivity in 22q11.2 deletion syndrome

Chromosome 22q11.2 deletion is among the strongest known genetic risk factors for neuropsychiatric disorders, including autism and schizophrenia. Brain imaging studies have reported disrupted large-scale functional connectivity in people with 22q11 deletion syndrome (22q11DS). However, the significance and biological determinants of these functional alterations remain unclear. Here, we use a cross-species design to investigate the developmental trajectory and neural underpinnings of brain dysconnectivity in 22q11DS. We find that LgDel mice, an established mouse model of 22q11DS, exhibit age-specific patterns of functional MRI (fMRI) dysconnectivity, with widespread fMRI hyper-connectivity in juvenile mice reverting to focal hippocampal hypoconnectivity over puberty. These fMRI connectivity alterations are mirrored by co-occurring developmental alterations in dendritic spine density, and are both transiently normalized by developmental GSK3{beta} inhibition, suggesting a synaptic origin for this phenomenon. Notably, analogous hyper-to hypoconnectivity reconfiguration occurs also in human 22q11DS, where it affects hippocampal and cortical regions spatially enriched for synaptic genes that interact with GSK3{beta}, and autism-relevant transcripts. Functional dysconnectivity in somatomotor components of this network is predictive of age-dependent social alterations in 22q11.2 deletion carriers. Taken together, these findings suggest that synaptic-related mechanisms underlie developmentally mediated functional dysconnectivity in 22q11DS.

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bioRxiv2022

Rhythmic oscillations in the midbrain dopaminergic nuclei in mice

Dopamine release in the forebrain by midbrain ventral tegmental nucleus (VTA) and substantia nigra pars compacta (SNpc) neurons is implicated in reward processing, goal-directed learning, and decision-making. Rhythmic oscillations of neural excitability underlie coordination of network processing, and have been reported in these dopaminergic nuclei at several frequency bands. This paper provides a comparative characterization of several frequencies of oscillations of local field potential and single unit activity, highlighting some behavioral correlates. We recorded from optogenetically identified dopaminergic sites in mice training in operant olfactory and visual discrimination tasks. Rayleigh and Pairwise Phase Consistency (PPC) analyses revealed some VTA/SNc neurons phase-locked to each frequency range, with fast spiking interneurons (FSIs) prevalent at 1-2.5 Hz (slow) and 4 Hz bands, and dopaminergic neurons predominant in the theta band. More FSIs than dopaminergic neurons were phase-locked in the slow and 4 Hz bands during many task events. The highest incidence of phase-locking in neurons was in the slow and 4 Hz bands, and occurred during the delay between the operant choice and trial outcome (reward or punishment) signals. These data provide a basis for further examination of rhythmic coordination of activity of dopaminergic nuclei with other brain structures, and its impact for adaptive behavior.

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bioRxiv2021

Astrocytic Regulation of Basal Ganglia Dopamine/D2-Dependent Behaviors

Astrocytic involvement in dopamine dynamics related to motivational and sensorimotor gating abilities is unknown. We found that dysbindin-1 (Dys1) hypofunction increases the activity of astrocytes, which express only the isoform Dys1A that is reduced in the caudate of patients with schizophrenia. Astrocytic Dys1A disruption resulted in avolition and sensorimotor gating deficits, increased astrocytic dopamine D2 receptors and decreased dopaminergic tone within basal ganglia. Notably, astrocytic Dys1A hypofunction disrupted dopamine dynamics linked to reward expectancy and interconnected with astrocytes Ca2+ responses mainly in the globus pallidus externus (GPe). Finally, we proved these phenotypes were mediated by D2 receptors in astrocytes as their selective deletion in astrocytes either in GPe or SNc/VTA enhanced motivation and sensorimotor gating abilities as well as dopaminergic release in the GPe. Therefore, astrocytes control motivational and sensorimotor gating processes through Dys1A/D2-dependent mechanisms within the basal ganglia.

neuroscience↗

bioRxiv2019

Acute and repeated intranasal oxytocin differentially modulate brain-wide functional connectivity

Central release of the neuropeptide oxytocin (OXT) modulates neural substrates involved in socio-affective behavior. This property has prompted research into the use of intranasal OXT administration as an adjunctive therapy for brain conditions characterized by social impairment, such as autism spectrum disorders (ASD). However, the neural circuitry and brain-wide functional networks recruited by intranasal OXT administration remain elusive. Moreover, little is known of the neuroadaptive cascade triggered by long-term administration of this peptide at the network level. To address these questions, we applied fMRI-based circuit mapping in adult mice upon acute and repeated (seven-day) intranasal dosing of OXT. We report that acute and chronic OXT administration elicit comparable fMRI activity as assessed with cerebral blood volume mapping, but entail largely different patterns of brain-wide functional connectivity. Specifically, acute OXT administration focally boosted connectivity within key limbic components of the rodent social brain, whereas repeated dosing led to a prominent and widespread increase in functional connectivity, involving a strong coupling between the amygdala and extended cortical territories. Importantly, this connectional reconfiguration was accompanied by a paradoxical reduction in social interaction and communication in wild-type mice. Our results identify the network substrates engaged by exogenous OXT administration, and show that repeated OXT dosing leads to a substantial reconfiguration of brain-wide connectivity, entailing an aberrant functional coupling between cortico-limbic structures involved in socio-communicative and affective functions. Such divergent patterns of network connectivity might contribute to discrepant clinical findings involving acute or long-term OXT dosing in clinical populations.

neuroscience↗