Biology subjects

Kooiker, C. L.

Publications and source records attributed to Kooiker, C. L..

5 recordsLinked to original sources

bioRxiv2026

Peptide signaling in the paraventricular thalamus contributes to disrupted adult reward behaviors after early-life adversity

Early-life adversity (ELA) is strongly linked to emotional disorders characterized by dysregulated reward behaviors including diminished motivation for and enjoyment of rewards (anhedonia). However, how transient ELA leads to enduring disruptions of reward behaviors remains unclear. Using activity-dependent genetic labeling during ELA, we previously found that the paraventricular thalamic nucleus (PVT) uniquely distinguishes ELA from typical rearing, and inhibiting ELA-activated PVT cells in adult ELA mice rescued reward behaviors in a sex-specific manner. However, the cellular mechanisms by which ELA alters the function of PVT neurons enduringly, to impact adult reward behaviors is unresolved. Here, we probed potential gene expression mechanisms by assessing reward-induced gene translation selectively in early-life activated (TRAPed) PVT cells, and identified genes regulated by reward in a sex-specific way. Combining data- and hypothesis-driven approaches, we targeted the corticotropin-releasing hormone receptor type 1 (CRHR1) as potentially mediating ELA-induced disruptions of reward behaviors. We find that CRISPR-Cas9-mediated Crhr1 deletion in TRAPed-PVT cells restores typical reward behaviors in ELA mice. Our results provide insight into the developmental origin of mental illness and identify potentially powerful molecular targets for prevention or mitigation of the consequences of ELA on reward behaviors germane to human mental illness.

neuroscience↗

bioRxiv2025

Inhibition of the Microglial Phagocytic Receptor MerTK Underlies ELA-induced Changes in Synapses and Behavior in Male Mice

BackgroundEarly-life adversity (ELA) is a significant risk factor for emotional disorders like depression, likely by provoking changes in stress-related circuit development. We have previously shown that ELA increases the number of excitatory synapses onto corticotropin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus (PVN) by decreasing microglial synapse engulfment. Here, we hypothesize that ELA induces microglial dysfunction via inhibition of the microglial phagocytic receptor, MerTK, thus resulting in the observed changes in synapses and stress-related behavior. MethodsTo determine whether deleting MerTK in microglia phenocopies the effects of ELA, microglia-specific (m)MerTK-KO (CX3CR1-Cre+::MerTKfl/fl) mice were crossed with wild-type (CX3CR1-Cre-::MerTKfl/fl) mice and their litters were reared in either a control or ELA (induced by limited bedding and nesting paradigm) environment, from postnatal days (P)2-10. Excitatory synapses in the PVN were assessed at P10, and adult offspring were tested in a behavioral battery to measure threat-response (known to be dependent on PVN-CRH+neurons) and anxiety-like behavior, followed by acute restraint stress to measure the neuroendocrine stress response. ResultsFollowing ELA at P10, excitatory, but not inhibitory, synapses in the PVN were increased in males, which was mimicked by mMerTK-KO in control males, but caused no further increase in ELA males. However, females already had higher numbers of excitatory synapses at baseline, and showed no further increase with ELA or mMerTK-KO. Remarkably, the pattern of threat-response behavior in males closely matched the excitatory synapses, with mMerTK-KO control males escaping more from the simulated predator threat in the looming-shadow threat task, similar to ELA males. Again, females did not show any significant changes due to ELA or mMerTK-KO in the threat-response, although they did show ELA-induced changes in anxiety-like behavior. ELA provoked a greater corticosterone response to acute stress in males, but not females, although females were again higher at baseline. ConclusionsOur results demonstrate that ELA provokes increased excitatory synapses in the PVN, leading to an increased active response to threat in the looming-shadow test in males only. Deleting MerTK specifically from microglia recapitulates both the synaptic and behavioral effects in control males, but does not have an effect in ELA males or control females, suggesting that the MerTK pathway is already inhibited by ELA in males and less active in females at baseline. Our work is the first to elucidate the mechanisms underlying the male-biased microglial dysfunction caused by ELA, with promise for the development of better preventative and therapeutic strategies for at-risk children.

neuroscience↗

bioRxiv2024

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

While links between early-life adversity (ELA) and mental illnesses characterized by dysregulated reward behaviors are well-established, the underlying mechanisms remain unclear. In mice, ELA reduces hedonic consumption and interest in sex reward in adult males and, in contrast, augments reward consumption in females. Here, using genetic tagging (TRAPing) we found robust, sex-specific activation of thalamic paraventricular nucleus (PVT) neurons during ELA. Manipulating these neurons in adults normalized reward behaviors: Blocking TRAPed anterior PVT neurons restored hedonic consumption in ELA males and augmented hedonic consumption in control females. In contrast, activation of these neurons reduced consumption in control males and ELA females. For posterior PVT, blocking TRAPed cells attenuated excessive reward consumption in ELA females and reduced it in control males. Thus, PVT is key for adaptive brain plasticity; anterior and posterior PVT carry different functions and contribute to the effects of ELA on adult reward behaviors in a sex-dependent manner.

neuroscience↗

bioRxiv2022

Genetic tagging uncovers a robust, selective activation of the thalamic paraventricular nucleus by adverse experiences early in life

BackgroundEarly-life adversity (ELA) is associated with increased risk for mood disorders including depression and substance use disorders. These 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 have identified aberrant reward-seeking behaviors, a discovery that provides a framework for assessing the underlying circuits. MethodsEmploying TRAP2 male and female mice, in which neurons activated within a defined timeframe 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 cFos labeling, we defined the molecular identity of this population of activated neurons. ResultsWe uniquely demonstrate that the TRAP2 system is feasible and efficacious in neonatal mice. Surprisingly, the paraventricular nucleus of the thalamus (PVT) is robustly and almost exclusively activated by ELA and is the only region distinguishing ELA from typical rearing. Remarkably, a large proportion of ELA-activated PVT neurons express CRFR1, the receptor for the stress-related peptide, corticotropin-releasing hormone (CRH), but these neurons do not express CRH itself. ConclusionsWe show here that the PVT, an important component of reward circuits which 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.

neuroscience↗

bioRxiv2021

Impaired developmental microglial pruning of excitatory synapses on CRH-expressing hypothalamic neurons exacerbates stress responses throughout life

The developmental origins of stress-related mental illnesses are well-established, and early-life stress/adversity (ELA) is an important risk factor. However, it is unclear how ELA impacts the maturation of salient brain circuits, provoking enduring vulnerability to stress and stress-related disorders. Here we find that ELA increases the number and function of excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, and implicate disrupted synapse pruning by microglia as a key mechanism. Microglial process dynamics on live imaging, and engulfment of synaptic elements by microglia, were both attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor Mer. Accordingly, selective chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Selective early-life microglial activation also mitigated the adrenal hypertrophy and prolonged stress responses in adult ELA mice, establishing microglial actions during development as powerful contributors to experience-dependent sculpting of stress-related brain circuits.

neuroscience↗