Unexpected Transcriptional Programs Contribute to Hippocampal Memory Deficits and Neuronal Stunting after Early-Life Adversity

Bolton, Jessica L.; Schulmann, Anton; Garcia-Curran, Megan M.; Regev, Limor; Chen, Yuncai; Kamei, Noriko; Shao, Manlin; Singh-Taylor, Akanksha; Jiang, Shan; Noam, Yoav; Molet, Jenny; Mortazavi, A; Baram, Tallie Z.

doi:10.1016/j.celrep.2020.108511

Cited by 28 publications

(18 citation statements)

References 119 publications

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“…Here, we demonstrate that as a result of ELA, microglia abutting CRH + neurons in the PVN engulf fewer synaptic elements compared with controls ( Figure 3 ), whereas synapse engulfment by microglia not in contact with CRH + neurons is unchanged ( Figure S2G ). These results suggest a selectivity of the neuronal targets of microglia within PVN, which may derive from altered signaling of CRH + cells to adjacent microglia as a result of ELA ( Bolton et al, 2020 ; Singh-Taylor et al, 2018 ). Alternatively, distinct microglia populations may be assigned to synapse pruning of specific neuronal populations within PVN.…”

Section: Discussionmentioning

confidence: 85%

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

et al. 2022

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Section: Discussionmentioning

confidence: 85%

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

et al. 2022

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“…Other crucial receptors in the PVT are acted upon by neuropeptide ligands, and these receptors and their ligands are often also expressed in gradients across the PVT. Neurotensin receptor type 1 and 2 are found in the PVT, as well their ligand, a neuropeptide that is expressed throughout the PVT but most densely at its anterior and posterior ends (Boudin et al, 1996;Sarret et al, 2003;Curtis et al, 2021). Neurotensin acts in the pPVT to decrease ethanol consumption and in the aPVT to increase exploratory behavior following chronic alcohol intake (Pandey et al, 2019;Pandey and Barson, 2020).…”

Section: Neuromodulators and The Pvtmentioning

confidence: 99%

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

Kooiker

Birnie

Baram

2021

Front. Behav. Neurosci.

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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.

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“…S3). These results suggest a selectivity of the neuronal targets of microglia, at least within the PVN, which may derive from altered signaling of CRH cells to adjacent microglia as a result of ELA 65,66 . Alternatively, distinct microglia populations may be assigned to synapse pruning of specific neuronal populations within the PVN.…”

Section: Discussionmentioning

confidence: 87%

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

Bolton

Short

Othy

et al. 2021

Preprint

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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.

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Unexpected Transcriptional Programs Contribute to Hippocampal Memory Deficits and Neuronal Stunting after Early-Life Adversity

Cited by 28 publications

References 119 publications

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

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

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

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

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