Biology subjects

Bravo-Rivera, H.

Publications and source records attributed to Bravo-Rivera, H..

5 recordsLinked to original sources

bioRxiv2025

Neuropeptidergic transmission shapes emergent properties of prefrontal cortical circuits underlying learning

The prefrontal cortex (PFC) is essential for top-down control of affect and its dysfunction is implicated in many psychiatric disorders. Inhibitory interneurons expressing somatostatin have been implicated in cognition, affect, and disease. However, somatostatins function as a neuropeptide transmitter remains unclear. Here, we investigated the contribution of somatostatin neurotransmission in differentiating between salient (rewarding or aversive) and neutral outcomes. Monitoring somatostatin release and somatostatin receptor antagonism revealed time-dependent regulation of outcome-specific associative learning during acquisition. We found that somatostatin transmission enables configural representations incorporating a salient, aversive outcome in prefrontal cortical neurons, and a threat-driven shift in population-level network activity in-vivo. These findings show a novel role for somatostatin, an interneuron "cellular marker", signaling in shaping learning and emergent network dynamics. Further this framework revealed that reduced somatostatin neuropeptidergic transmission may impair top-down control of affective behaviors observed in mental health disorders, suggesting potential new avenues for therapeutic intervention.

neuroscience↗

bioRxiv2024

A novel epigenetic clock for rhesus macaques unveils an association between early life adversity and epigenetic age acceleration

Because DNA methylation changes reliably with age, machine learning models called epigenetic clocks can estimate an individuals age based on their DNA methylation profile. This epigenetic measure of age can deviate from ones true age, and the difference between the epigenetic age and true age, known as epigenetic age acceleration (EAA), has been found to directly correlate with morbidity and mortality in adults. Emerging evidence suggests that EAA is also associated with aberrant health outcomes in children, making epigenetic clocks useful tools for studying aging and development. We developed two highly accurate epigenetic clocks for the rhesus macaque, utilizing 1,008 blood samples from 690 macaques between 2 days and 23.4 years of age with diverse genetic backgrounds and exposure to environmental conditions. The first clock, which is trained on all samples, achieves a Pearson correlation between true age and predicted age of 0.983 and median absolute error of 0.210 years. To study phenotypes during development, the second clock is optimized for macaques younger than 6 years and achieves a Pearson correlation of 0.974 and a median absolute error of 0.148 years. Using the latter clock, we investigated whether epigenetic aging is affected by early life adversity in the form of infant maltreatment. Our data suggests that maltreatment and increased hair cortisol levels are associated with epigenetic age acceleration right after the period of maltreatment.

neuroscience↗

bioRxiv2024

Prefrontal cortical dynorphin peptidergic transmission constrains threat-driven behavioral and network states

Prefrontal cortical (PFC) circuits provide top-down control of threat reactivity. This includes ventromedial PFC (vmPFC) circuitry, which plays a role in suppressing fear-related behavioral states. Dynorphin (Dyn) has been implicated in mediating negative affect and mal-adaptive behaviors induced by severe threats and is expressed in limbic circuits, including the vmPFC. However, there is a critical knowledge gap in our understanding of how vmPFC Dyn-expressing neurons and Dyn transmission detect threats and regulate expression of defensive behaviors. Here, we demonstrate that Dyn cells are broadly activated by threats and release Dyn locally in the vmPFC to limit passive defensive behaviors. We further demonstrate that vmPFC Dyn-mediated signaling promotes a switch of vmPFC networks to a fear-related state. In conclusion, we reveal a previously unknown role of vmPFC Dyn neurons and Dyn neuropeptidergic transmission in suppressing defensive behaviors in response to threats via state-driven changes in vmPFC networks. Highlights[bullet] vmPFCDyn neurons are activated by threats and threat-predictive cues [bullet]Characterization of a genetically-encoded kappa-opioid receptor sensor [bullet]vmPFCDyn neurons rapidly release Dyn in response to threats and their predictors [bullet]vmPFCDyn signaling opposes threat-induced passive defensive behaviors [bullet]Dyn signaling promotes threat-evoked state transitions in vmPFC networks

neuroscience↗

bioRxiv2020

Innate fear responses are reflected in the blood epigenome of rhesus macaques.

AO_SCPLOWBSTRACTC_SCPLOWFear and anxiety are complex physiological states aimed at promoting adaptive behaviors. They are also core symptoms of many neuropsychiatric disorders; yet, our knowledge of the underlying biological correlates remains fragmented. Non-human primate models are critical for our understanding of mechanisms associated with complex higher-order behavioral phenotypes. Here we investigated individual variations in innate fear responses to a snake stimulus in free-ranging rhesus macaques and discovered an unusual bimodal distribution of fearful and fearless behavior, likely as a result of an environmental insult by a hurricane. In a translational approach, we discovered a DNA methylation profile associated with fear behavior in these monkeys. We also found evidence that this epigenetic signature is associated with innate fear responses in humans in the form of acoustic startle. Our data highlight the importance and translational utility of non-human primate models for neuropsychiatric research and provide a potential epigenetic signature of innate fear.

neuroscience↗

bioRxiv2018

Individual variability in behavior and functional networks predicts vulnerability using a predator scent model of PTSD

Only a minority of individuals who experience traumatic event(s) subsequently develop post-traumatic stress disorder (PTSD). However, whether differences in vulnerability to PTSD result from predisposition or a consequence of trauma exposure remains unclear. A major challenge in differentiating these possibilities is that clinical studies focus on individuals already exposed to traumatic experiences, and do not take into account pre-trauma conditions. Here using the predator scent model of PTSD in rats and a longitudinal design, we measured pre-trauma brain-wide neural circuit functional connectivity (FC), behavioral and corticosterone responses to trauma exposure, and post-trauma anxiety. Individual differences in freezing responses to predator scent exposure correlated with differences in pre-trauma FC in a set of neural circuits, especially in olfactory and stress-related systems, indicating that pre-existing function in these circuits could predispose animals to differential fearful responses to threats. Counterintuitively, rats with the lowest freezing showed more avoidance of the predator scent, a prolonged corticosterone response, and higher anxiety long after exposure. This study provides a comprehensive framework of pre-existing circuit function that determines threat response strategy, which might be directly related to the development of PTSD-like behaviors.

neuroscience↗