All mammals transition from breastfeeding to independent feeding during the lactation period. In humans and other mammals, this critical transition is important for later in life metabolic control and, consequently, for the development of many chronic conditions. Here, Dr. Dietrich will discuss the work of his lab studying the function of hypothalamic neurons involved in homeostatic control during the transition from breastfeeding to independent feeding. His work illuminates novel properties of hypothalamic neurons in early life, suggesting mechanisms by which early life events shape homeostatic regulation throughout the individual’s lifespan.

Interoception, the sense of internal bodily signals, is essential for physiological homeostasis, cognition, and emotions. While human insular cortex (InsCtx) is implicated in interoception, the cellular and circuit mechanisms remain unclear. I will describe our recent work imaging mouse InsCtx neurons during two physiological deficiency states – hunger and thirst. InsCtx ongoing activity patterns reliably tracked the gradual return to homeostasis, but not changes in behavior. Accordingly, while artificial induction of hunger/thirst in sated mice via activation of specific hypothalamic neurons (AgRP/SFOGLUT) restored cue-evoked food/water-seeking, InsCtx ongoing activity continued to reflect physiological satiety. During natural hunger/thirst, food/water cues rapidly and transiently shifted InsCtx population activity to the future satiety-related pattern. During artificial hunger/thirst, food/water cues further shifted activity beyond the current satiety-related pattern. Together with circuit-mapping experiments, these findings suggest that InsCtx integrates visceral-sensory inputs regarding current physiological state with hypothalamus-gated amygdala inputs signaling upcoming ingestion of food/water, to compute a prediction of future physiological state.

Puberty is a brain-driven phenomenon, which is under the control of sophisticated regulatory networks that integrate a large number of endogenous and environmental signals, including metabolic and nutritional cues. Puberty onset is tightly bound to the state of body energy reserves, and deregulation of energy/metabolic homeostasis is often associated with alterations in the timing of puberty. However, despite recent progress in the field, our knowledge of the specific molecular mechanisms and pathways whereby our brain decode metabolic information to modulate puberty onset remains fragmentary and incomplete. Compelling evidence, gathered over the last fifteen years, supports an essential role of hypothalamic neurons producing kisspeptins, encoded by Kiss1, in the neuroendocrine control of puberty. Kiss1 neurons are major components of the hypothalamic GnRH pulse generator, whose full activation is mandatory pubertal onset. Kiss1 neurons seemingly participate in transmitting the regulatory actions of metabolic cues on pubertal maturation. However, the modulatory influence of metabolic signals (e.g., leptin) on Kiss1 neurons might be predominantly indirect and likely involves also the interaction with other transmitters and neuronal populations. In my presentation, I will review herein recent work of our group, using preclinical models, addressing the molecular mechanisms whereby Kiss1 neurons are modulated by metabolic signals, and thereby contribute to the nutritional control of puberty. In this context, the putative roles of the energy/metabolic sensors, AMP-activated protein kinase (AMPK) and SIRT1, in the metabolic control of Kiss1 neurons and puberty will be discussed. In addition, I will summarize recent findings from our team pointing out a role of central de novo ceramide signaling in mediating the impact of obesity of (earlier) puberty onset, via non-canonical, kisspeptin-related pathways. These findings are posed of translational interest, as perturbations of these molecular pathways could contribute to the alterations of pubertal timing linked to conditions of metabolic stress in humans, ranging from malnutrition to obesity, and might become druggable targets for better management of pubertal disorders.

Obesity and neurodegeneration lead to millions of premature deaths each year and lack broadly effective treatments. Obesity is largely caused by the abnormal function of cell populations in the hypothalamus that regulate appetite. We have developed methods generate human hypothalamic neurons from hPSCs to study how they respond to nutrients and hormones (e.g. leptin) and how disease-associated mutations alter their function. Since human hypothalamic neurons can be produced in large numbers, are functionally responsive, have a human genome that can be readily edited, and are in culture environment that can be readily controlled, there is an unprecedented opportunity to study the genetic and environmental factors underlying obesity. In addition, we are fascinated by the fact that mid-life obesity is a risk factor for dementia later in life, and caloric restriction, exercise, and certain anti-obesity drugs are neuroprotective, suggesting that there are shared mechanisms between obesity and neurodegeneration. Studies of HPSC-derived hypothalamic neurons may help bridge the mechanistic gulf between human genetic data and organismic phenotypes, revealing new therapeutic targets. ​