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Tracking net body movement in real time may enable the brain to estimate ongoing demands and thus better orchestrate muscle tone, energy balance, and arousal. To identify neural populations specializing in tracking net body movement, here, we compared self-initiated movement-related activity across genetically-defined subcortical neurons in the mouse brain, including dopaminergic, glutamatergic, noradrenergic, and key peptidergic neurons. We show that hypothalamic orexin/hypocretin-producing neurons (HONs) are exceptionally precise movement-trackers, encoding net body movement across multiple classified behaviors with a high degree of precision, independent of head acceleration. This tracking was so precise that video analysis of the mouse body movement reliably served as a low-cost biometric for HON population activity. The movement tracking was independent of internal nutritional states, and occurred in a communication bandwidth distinct from HON encoding of blood glucose. At key projection targets, orexin/hypocretin peptide outputs correlated with self-initiated movement in a projection-specific manner, indicating functional heterogeneity in HON outputs. Finally, we found that body movement was not encoded to the same extent in other key neural populations related to arousal or energy. These findings indicate that subcortical orchestrators of arousal and metabolism are finely tuned to encode net body movement, constituting a bridge multiplexing ongoing motor activity with internal energy resources.

Obesity has long been identified as a global epidemic with major health implications such as diabetes and cardiovascular disease. Maternal overnutrition leads to significant health issues in industrial countries and is one of the risk factors for the development of obesity and related disorders in the progeny. The wide accessibility of junk food in recent years is one of the major causes of obesity, as it is low in nutrient content and usually high in salt, sugar, fat, and calories. An excess of nutrients during fetal life not only has immediate effects on the fetus, including increased growth and fat deposition in utero , but also has long-term health consequences. Based on human studies, it is difficult to discern between genetic and environmental contributions to the risk of disease in future generations. Consequently, animal models are essential for studying the impact of maternal overnutrition on the developing offspring. Recently, animal models provided some insight into the physiological mechanisms that underlie developmental programming. Most of the studies employed thus far have focused only on obesity and metabolic dysfunctions in the offspring. These studies have advanced our understanding of how maternal overnutrition in the form of high-fat diet exposure can lead to an increased risk of obesity in the offspring, but many questions remain open. How maternal overnutrition may increase the risk of developing brain pathology such as cognitive disabilities in the offspring and increase the risk to develop metabolic disorders later in life? Further, does maternal overnutrition exacerbate cognitive- and cardio-metabolic aging in the offspring?

The unabated rise in obesity prevalence during the last 40 years has spurred substantial interest in understanding the reasons for this epidemic. Studies in mice and humans have demonstrated that obesity is a highly heritable disease; however genetic variations within specific populations have so far not been able to explain this phenomenon to its full extent. Recent work has demonstrated that environmental cues can be sensed by an organism to elicit lasting changes, which in turn can affect systemic energy metabolism by different epigenetic mechanisms such as changes in small noncoding RNA expression, DNA methylation patterns, as well as histone modifications. These changes can directly modulate cellular function in response to environmental cues, however research during the last decade has demonstrated that some of these modifications might be transmitted to subsequent generations, thus modulating energy metabolism of the progeny in an inter‐ as well as transgenerational manner. In this context, adipose tissue has become a focus of research due to its plasticity, which allows the formation of energy storing (white) as well as energy wasting (brown/brite/beige) cells within the same depot. In this Review, the effects of environmental induced obesity with a particular focus on adipose tissue are discussed. It has been established that environmental cues can be sensed by an organism, thus affecting metabolism through different epigenetic mechanisms such as small noncoding RNAs, DNA methylation, and histone modifications. These changes can directly modulate cellular function and might be transmitted to subsequent generations, modulating metabolism in an inter‐ and transgenerational manner. In this Review, the effects of environmental induced obesity with a focus on adipose tissue are discussed.

There is a growing body of evidence linking maternal overnutrition to obesity and psychopathology that can be conserved across multiple generations. Recently, we demonstrated in a maternal high-fat diet (HFD; MHFD) mouse model that MHFD induced enhanced hedonic behaviors and obesogenic phenotypes that were conserved across three generations via the paternal lineage, which was independent of sperm methylome changes. Here, we show that sperm tRNA-derived small RNAs (tsRNAs) partly contribute to the transmission of such phenotypes. We observe increased expression of sperm tsRNAs in the F1 male offspring born to HFD-exposed dams. Microinjection of sperm tsRNAs from the F1-HFD male into normal zygotes reproduces obesogenic phenotypes and addictive-like behaviors, such as increased preference of palatable foods and enhanced sensitivity to drugs of abuse in the resultant offspring. The expression of several of the differentially expressed sperm tsRNAs predicted targets such as CHRNA2 and GRIN3A, which have been implicated in addiction pathology, are altered in the mesolimbic reward brain regions of the F1-HFD father and the resultant HFD-tsRNA offspring. Together, our findings demonstrate that sperm tsRNA is a potential vector that contributes to the transmission of MHFD-induced addictive-like behaviors and obesogenic phenotypes across generations, thereby emphasizing its role in diverse pathological outcomes.

Brain orexin (hypocretin) neurons are implicated in sleep–wake switching and reward-seeking but their roles in rapid arousal dynamics and reward perception are unclear. Here, cell-specific stimulation, deletion and in vivo recordings revealed strong correlative and causal links between pupil dilation—a quantitative arousal marker—and orexin cell activity. Coding of arousal and reward was distributed across orexin cells, indicating that they specialize in rapid, multiplexed communication of momentary arousal and reward states. The biological meaning of eye pupil size is a subject of intense research. This study shows that pupil fluctuations reveal information about hypothalamic orexin cells, which control pupil size via a noradrenaline neural circuit.

Lateral hypothalamic (LH) hypocretin/orexin neurons (HONs) control brain-wide electrical excitation. Abnormally high excitation produces epileptic seizures, which affect millions of people and need better treatments. HON population activity spikes from minute to minute, but the role of this in seizures is unknown. Here, we describe correlative and causal links between HON activity spikes and seizures. Applying temporally-targeted HON recordings and optogenetic silencing to a male mouse model of acute epilepsy, we found that pre-seizure HON activity predicts and controls the electrophysiology and behavioral pathology of subsequent seizures. No such links were detected for HON activity during seizures. Having thus defined the time window where HONs influence seizures, we targeted it with LH deep brain stimulation (DBS), which inhibited HON population activity, and produced seizure protection. Collectively, these results uncover a feature of brain activity linked to seizures, and demonstrate a proof-of-concept treatment that controls this feature and alleviates epilepsy. Epileptic seizures need better treatments. Here, the authors show that seizure intensity is predicted and controlled by pre-seizure activity of hypothalamic orexin cells, and can be reduced by a hypothalamic deep brain stimulation.

Learning to fear danger is essential for survival. However, overactive, relapsing fear behavior in the absence of danger is a hallmark of disabling anxiety disorders that affect millions of people. Its suppression is thus of great interest, but the necessary brain components remain incompletely identified. We studied fear suppression through a procedure in which, after acquiring fear of aversive events (fear learning), subjects were exposed to fear-eliciting cues without aversive events (safety learning), leading to suppression of fear behavior (fear extinction). Here we show that inappropriate, learning-resistant fear behavior results from disruption of brain components not previously implicated in this disorder: hypothalamic melanin-concentrating hormone–expressing neurons (MNs). Using real-time recordings of MNs across fear learning and extinction, we provide evidence that fear-inducing aversive events elevate MN activity. We find that optogenetic disruption of this MN activity profoundly impairs safety learning, abnormally slowing down fear extinction and exacerbating fear relapse. Importantly, we demonstrate that the MN disruption impairs neither fear learning nor related sensory responses, indicating that MNs differentially control safety and fear learning. Thus, we identify a neural substrate for inhibition of excessive fear behavior.

Recent research has focused on environmental effects that control tissue functionality and systemic metabolism. However, whether such stimuli affect human thermogenesis and body mass index (BMI) has not been explored. Here we show retrospectively that the presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring. Integrated analyses of the DNA methylome and RNA sequencing of the sperm from male mice revealed several clusters of co-regulated differentially methylated regions (DMRs) and differentially expressed genes (DEGs), suggesting that the improved metabolic health of the offspring was due to enhanced BAT formation and increased neurogenesis. The conclusions are supported by cell-autonomous studies in the offspring that demonstrate an enhanced capacity to form mature active brown adipocytes, improved neuronal density and more norepinephrine release in BAT in response to cold stimulation. Taken together, our results indicate that in humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia. How heavy a person is and how much active brown fat they have depends on their father and the season in which they were conceived.

Based on the human epidemiological association between prenatal infection and higher risk of schizophrenia, a number of animal models have been established to explore the long-term brain and behavioral consequences of prenatal immune challenge. Accumulating evidence suggests that the vulnerability to specific forms of schizophrenia-related abnormalities is critically influenced by the precise timing of the prenatal immunological insult. In the present study, we tested the hypothesis whether late prenatal immune challenge in mice may induce long-term behavioral and neurochemical dysfunctions primarily associated with the negative symptoms of schizophrenia. We found that prenatal exposure to the viral mimic polyriboinosinic-polyribocytidilic acid (Poly-I:C; 5 mg/kg, i.v.) on gestation day (GD) 17 led to significant deficits in social interaction, anhedonic behavior, and alterations in the locomotor and stereotyped behavioral responses to acute apomorphine (APO) treatment in both male and female offspring. In addition, male but not female offspring born to immune challenged mothers displayed behavioral/cognitive inflexibility as indexed by the presence of an abnormally enhanced latent inhibition (LI) effect. Prenatal immune activation in late gestation also led to numerous, partly sex-specific changes in basal neurotransmitter levels, including reduced dopamine (DA) and glutamate contents in the prefrontal cortex and hippocampus, as well as reduced γ -aminobutyric acid (GABA) and glycine contents in the hippocampus and prefrontal cortex, respectively. The constellation of behavioral and neurochemical abnormalities emerging after late prenatal Poly-I:C exposure in mice leads us to conclude that this immune-based experimental model provides a powerful neurodevelopmental animal model especially for (but not limited to) the negative symptoms of schizophrenia.

Background: Maternal overnutrition critically influences offspring’s long-term metabolic and cognitive health. While prior research indicates maternal diet can disrupt hippocampal function, the specific impact on spatial memory remains unclear. Methods: Female mice were fed a high-fat diet (HFD) for nine weeks before and during pregnancy. Offspring were weaned onto a standard diet and tested at postnatal day 90 using the dry maze, a spatial reference memory task. Results: HFD-exposed offspring exhibited significant learning acquisition impairments, with prolonged latencies in locating hidden rewards and diminished within-session improvements compared to controls. During the probe trial, they spent significantly less time in the target quadrant, indicating long-term spatial memory retention deficits. Notably, these cognitive impairments occurred independently of body weight differences at testing. Discussion: This study uniquely demonstrates that maternal HFD exposure induces specific spatial memory deficits in adult offspring, potentially through neurodevelopmental alterations preceding metabolic dysfunction. The results highlight the importance of prenatal nutrition in shaping cognitive outcomes later in life. Conclusions: These findings extend our understanding of how prenatal nutrition impacts cognitive aging and disease susceptibility. Given rising obesity rates among women of reproductive age, this research underscores the urgent need for targeted interventions to mitigate the intergenerational effects of maternal overnutrition on brain function.