Paraventricular Thalamus Neuronal Ensembles Encode Early-life Adversity and Mediate the Consequent Sex-dependent Disruptions of Adult Reward Behaviors.

Early-life adversity increases risk for mental illnesses including depression and substance use disorders, disorders characterized by dysregulated reward behaviors. However, the mechanisms by which transient ELA enduringly impacts reward circuitries are not well understood. In mice, ELA leads to anhedonia-like behaviors in males and augmented motivation for palatable food and sex-reward cues in females. Here, the use of genetic tagging demonstrated robust, preferential, and sex-specific activation of the paraventricular nucleus of the thalamus (PVT) during ELA and a potentiated reactivation of these PVT neurons during a reward task in adult ELA mice. Chemogenetic manipulation of specific ensembles of PVT neurons engaged during ELA identified a role for the posterior PVT in ELA-induced aberrantly augmented reward behaviors in females. In contrast, anterior PVT neurons activated during ELA were required for the anhedonia-like behaviors in males. Thus, the PVT encodes adverse experiences early-in life, prior to the emergence of the hippocampal memory system, and contributes critically to the lasting, sex-modulated impacts of ELA on reward behaviors.

Genetic Tagging Uncovers a Robust, Selective Activation of the Thalamic Paraventricular Nucleus by Adverse Experiences Early in Life.

Background: Early-life adversity (ELA) is associated with increased risk for mood disorders, including depression and substance use disorders. These disorders are characterized by impaired reward-related behaviors, suggesting compromised operations of reward-related brain circuits. However, the brain regions engaged by ELA that mediate these enduring consequences of ELA remain largely unknown. In an animal model of ELA, we identified aberrant reward-seeking behaviors, a discovery that provides a framework for assessing the underlying circuits. Methods: Employing TRAP2 (targeted recombination in active populations) male and female mice, in which neurons activated within a defined time frame are permanently tagged, we compared ELA- and control-reared mice, assessing the quantity and distribution of ELA-related neuronal activation. After validating the TRAP2 results using native c-Fos labeling, we defined the molecular identity of this population of activated neurons. Results: We uniquely demonstrated that the TRAP2 system is feasible and efficacious in neonatal mice. Surprisingly, the paraventricular nucleus of the thalamus was robustly and almost exclusively activated by ELA and was the only region distinguishing ELA from typical rearing. Remarkably, a large proportion of ELA-activated paraventricular nucleus of the thalamus neurons expressed CRF1, the receptor for the stress-related peptide, corticotropin-releasing hormone, but these neurons did not express corticotropin-releasing hormone itself. Conclusions: The paraventricular nucleus of the thalamus, an important component of reward circuits that is known to encode remote, emotionally salient experiences to influence future motivated behaviors, encodes adverse experiences as remote as those occurring during the early postnatal period and is thus poised to contribute to the enduring deficits in reward-related behaviors consequent to ELA.

Early stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses.

Several mental illnesses, characterized by aberrant stress reactivity, often arise after early-life adversity (ELA). However, it is unclear how ELA affects stress-related brain circuit maturation, provoking these enduring vulnerabilities. We find that ELA increases functional excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, resulting from disrupted developmental synapse pruning by adjacent microglia. Microglial process dynamics and synaptic element engulfment were attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor MerTK. Accordingly, selective chronic chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Notably, selective early-life activation of ELA microglia normalized adult acute and chronic stress responses, including stress-induced hormone secretion and behavioral threat responses, as well as chronic adrenal hypertrophy of ELA mice. Thus, microglial actions during development are powerful contributors to mechanisms by which ELA sculpts the connectivity of stress-regulating neurons, promoting vulnerability to stress and stress-related mental illnesses.

The Paraventricular Thalamus: A Potential Sensor and Integrator of Emotionally Salient Early-Life Experiences.

Early-life experiences influence a broad spectrum of behaviors throughout the lifespan that contribute to resilience or vulnerability to mental health disorders. Yet, how emotionally salient experiences early in life are encoded, stored, and processed and the mechanisms by which they influence future behaviors remain poorly understood. The paraventricular nucleus of the thalamus (PVT) is a key structure in modulating positive and negative experiences and behaviors in adults. However, little is known of the PVT's role in encoding and integrating emotionally salient experiences that occur during neonatal, infancy, and childhood periods. In this review, we (1) describe the functions and connections of the PVT and its regulation of behavior, (2) introduce novel technical approaches to elucidating the role of the PVT in mediating enduring changes in adult behaviors resulting from early-life experiences, and (3) conclude that PVT neurons of neonatal rodents are engaged by both positive and negative emotionally salient experiences, and their activation may enduringly govern future behavior-modulating PVT activity during emotionally salient contexts.

Plasticity of the Reward Circuitry After Early-Life Adversity: Mechanisms and Significance.

Disrupted operation of the reward circuitry underlies many aspects of affective disorders. Such disruption may manifest as aberrant behavior including risk taking, depression, anhedonia, and addiction. Early-life adversity is a common antecedent of adolescent and adult affective disorders involving the reward circuitry. However, whether early-life adversity influences the maturation and operations of the reward circuitry, and the potential underlying mechanisms, remain unclear. Here, we present novel information using cutting-edge technologies in animal models to dissect out the mechanisms by which early-life adversity provokes dysregulation of the complex interactions of stress and reward circuitries. We propose that certain molecularly defined pathways within the reward circuitry are particularly susceptible to early-life adversity. We examine regions and pathways expressing the stress-sensitive peptide corticotropin-releasing factor (CRF), which has been identified in critical components of the reward circuitry and interacting stress circuits. Notably, CRF is strongly modulated by early-life adversity in several of these brain regions. Focusing on amygdala nuclei and their projections, we provide evidence suggesting that aberrant CRF expression and function may underlie augmented connectivity of the nucleus accumbens with fear/anxiety regions, disrupting the function of this critical locus of pleasure and reward.