Biology subjects

Lockhart, S.

Publications and source records attributed to Lockhart, S..

3 recordsLinked to original sources

bioRxiv2025

Adaptive thermogenesis reprograms the behavioural and metabolic responses to protein restriction for successful amino acid homeostasis

Reduced protein intake is proposed to contribute to the obesity epidemic, but existing murine models of protein restriction do not promote obesity, limiting insight into underlying mechanisms. Here we show that mice self-select a consistent daily protein intake, independent of energy needs. Under mild protein restriction (7-10% protein), mice exhibit hyperphagia and increased adiposity. This hyperphagic response is blunted at thermoneutrality, leading to loss of lean mass and body weight. Protein-restricted mice also fail to exhibit protein preference at thermoneutrality, despite elevated circulating FGF21 levels. Circulating levels of essential amino acids (AAs) are tightly regulated during protein restriction at 22{degrees}C, but this regulation is lost at 28{degrees}C. Metabolomic and transcriptional analyses revealed a role for hepatic and brown fat AA-derived acylcarnitines and N-acetyl AAs in buffering free AA levels for the maintenance of AA homeostasis at 22{degrees}C, but these pathways are blunted at thermoneutrality. Thus, the behavioural and metabolic adaptations to protein restriction rely on coordinated peripheral and central mechanisms, modulated by ambient temperature. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=63 SRC="FIGDIR/small/667623v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@1d1a9e1org.highwire.dtl.DTLVardef@1e7f3b5org.highwire.dtl.DTLVardef@131276borg.highwire.dtl.DTLVardef@130757_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2021

The anterior insular cortex associates temporally discontiguous stimuli during threat learning

Learning about potential threats in the environment is indispensable for survival. Deficits in threat learning constitute a key dimension of multiple brain disorders, which include posttraumatic stress disorder and anxiety disorder. While human brain imaging studies have highlighted a reliable engagement of the anterior insular cortex (AIC) in threat learning, its precise role remains elusive partly due to the lack of animal studies that can address causality and mechanistic questions. Filling in this gap, the present mouse study proposes a novel AIC-mediated mechanism underlying the association of temporally discontiguous stimuli during threat learning. We identified that activity of AIC layer 5 (L5) pyramidal neurons is required for associating temporally discontiguous stimuli, specifically during a time interval between them. Notably, the AIC is not required for associating temporally contiguous stimuli during threat learning. The AIC not only sends the essential information, via its L5 pyramidal neurons, to the basolateral amygdala (BLA) during the time interval, but also receives from the BLA. We also identified a modulatory role of AIC dopamine D1 receptor (D1R)-mediated dopamine signaling in associating temporally discontiguous stimuli during the time interval.

neuroscience↗

bioRxiv2021

Early life stress-induced vulnerability to postpartum mental disturbance: prolonged dysregulation of the HPA axis and behavior

Stress during childhood and adolescence increases the risk for postpartum depression (PPD). Patients with depression who have experienced adverse life events tend to be treatment refractory. However, the mechanism by which stress during childhood and adolescence are involved in the pathophysiology of PPD remains unclear. We investigated the longitudinal effects of adolescent stress on the hypothalamic-pituitary-adrenal (HPA) axis and behaviors in the postpartum period through mouse and human studies. We observed that adolescent social isolation caused an aberrantly sustained elevation of glucocorticoids via dysregulation of the HPA axis, leading to long-lasting postpartum behavioral changes in female mice. The postpartum behavioral changes elicited by this adolescent stress were not ameliorated by the medicines currently used for PPD treatment. However, a post-delivery treatment with a glucocorticoid receptor antagonist effectively ameliorated the behavioral changes in mice. We also demonstrated a significant impact of stress during childhood and adolescence on the HPA axis dysregulation and PPD in women. We provide experimental evidence that suggests a mechanism-driven therapeutic strategy (repurposing a GR antagonist) for at least some cases of treatment refractory PPD.

molecular biology↗