Exploratory rearing is governed by hypothalamic MCH neurons according to locus coeruleus.

Information seeking, such as standing on tiptoes to look around in humans, is observed across animals and helps survival. Its rodent analog - unsupported rearing on hind legs - was a classic model in deciphering neural signals of cognition, and is of intense renewed interest in preclinical modeling of neuropsychiatric states. Neural signals and circuits controlling this dedicated decision to seek information remain largely unknown. While studying sub-second timing of spontaneous behavioral acts and activity of MCH neurons (MNs) in behaving male and female mice, we observed large MN activity spikes that aligned to unsupported rears. Complementary causal, loss and gain of function, analyses revealed specific control of rear frequency and duration by MNs and MCHR1 receptors. Activity in a key stress center of the brain - the locus coeruleus noradrenaline cells - rapidly inhibited MNs, and required functional MCH receptors for its endogenous modulation of rearing. By defining a neural module that both tracks and controls rearing, these findings may facilitate further insights into biology of information seeking.Significance Statement Animals, including humans, use movement to interact with their environment - to reach specific targets or gain information, as when standing tall and looking around. Information-seeking is a fundamental behavior related to cognition and neuropsychiatric states. However, the neural circuits underlying it are still unclear. We show that hypothalamic neurons make melanin-concentrating hormone ("MN") are active during a well-known rodent analog of information-seeking - rearing on hind limbs - and contribute to driving these acts of rearing. We also find that locus coeruleus noradrenergic neurons, known for mediating stress responses, inhibit MNs, thus providing a neural link between stress and information-seeking. These results identify a neural substrate of information-seeking, and provide insights into how the brain toggles between conflicting, survival-critical priorities.

Transient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy.

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.

Disentangling the role of NAc D1 and D2 cells in hedonic eating.

Overeating is driven by both the hedonic component ('liking') of food, and the motivation ('wanting') to eat it. The nucleus accumbens (NAc) is a key brain center implicated in these processes, but how distinct NAc cell populations encode 'liking' and 'wanting' to shape overconsumption remains unclear. Here, we probed the roles of NAc D1 and D2 cells in these processes using cell-specific recording and optogenetic manipulation in diverse behavioral paradigms that disentangle reward traits of 'liking' and 'wanting' related to food choice and overeating in healthy mice. Medial NAc shell D2 cells encoded experience-dependent development of 'liking', while D1 cells encoded innate 'liking' during the first food taste. Optogenetic control confirmed causal links of D1 and D2 cells to these aspects of 'liking'. In relation to 'wanting', D1 and D2 cells encoded and promoted distinct aspects of food approach: D1 cells interpreted food cues while D2 cells also sustained food-visit-length that facilitates consumption. Finally, at the level of food choice, D1, but not D2, cell activity was sufficient to switch food preference, programming subsequent long-lasting overconsumption. By revealing complementary roles of D1 and D2 cells in consumption, these findings assign neural bases to 'liking' and 'wanting' in a unifying framework of D1 and D2 cell activity.

Control and coding of pupil size by hypothalamic orexin neurons.

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.

Maternal Over- and Malnutrition and Increased Risk for Addictive and Eating Disorders in the Offspring.

Evidence from human and animal studies has shown that maternal overnutrition and/or obesity are linked with neurobehavioral changes in the offspring. This fetal programming is characterized by adaptive responses to changes in the nutritional state during early life. In the past decade, an association has been made between overconsumption of highly-palatable food by the mother during fetal development and abnormal behaviors resembling addiction in the offspring. Maternal overnutrition can lead to alterations in the offspring's brain reward circuitry leading to hyperresponsiveness of this circuit following exposure to calorie-dense foods later in life. Given the accumulating evidence indicating that the central nervous system plays a pivotal role in regulating food intake, energy balance, and the motivation to seek food, a dysfunction in the reward circuitry may contribute to the addiction-like behaviors observed in the offspring. However, the underlying mechanisms leading to these alterations in the reward circuitry during fetal development and their relevance to the increased risk for the offspring to later develop addictive-like behaviors is still unclear. Here, we review the most relevant scientific reports about the impact of food overconsumption during fetal development and its effect on addictive-like behaviors of the offspring in the context of eating disorders and obesity.

Eat, seek, rest? An orexin/hypocretin perspective.

Seeking and ingesting nutrients is an essential cycle of life in all species. In classical neuropsychology these two behaviours are viewed as fundamentally distinct from each other, and known as appetitive and consummatory, respectively. Appetitive behaviour is highly flexible and diverse, but typically involves increased locomotion and spatial exploration. Consummatory behaviour, in contrast, typically requires reduced locomotion. Another long-standing concept is "rest and digest", a hypolocomotive response to calorie intake, thought to facilitate digestion and storage of energy after eating. Here, we note that the classical seek➔ingest➔rest behavioural sequence is not evolutionarily advantageous for all ingested nutrients. Our limited stomach capacity should be invested wisely, rather than spent on the first available nutrient. This is because nutrients are not simply calories: some nutrients are more essential for survival than others. Thus, a key choice that needs to be made soon after ingestion: to eat more and rest, or to terminate eating and search for better food. We offer a perspective on recent work suggesting how nutrient-specific neural responses shape this choice. Specifically, the hypothalamic hypocretin/orexin neurons (HONs) - cells that promote hyperlocomotive explorative behaviours - are rapidly and differentially modulated by different ingested macronutrients. Dietary non-essential (but not essential) amino acids activate HONs, while glucose depresses HONs. This nutrient-specific HON modulation engages distinct reflex arcs, seek➔ingest➔seek and seek➔ingest➔rest, respectively. We propose that these nutri-neural reflexes evolved to facilitate optimal nutrition despite the limitations of our body.

Something to Snack on: Can Dietary Modulators Boost Mind and Body?

The last decades have shown that maintaining a healthy and balanced diet can support brain integrity and functionality, while an inadequate diet can compromise it. However, still little is known about the effects and utility of so-called healthy snacks or drinks and their immediate short-term effects on cognition and physical performance. Here, we prepared dietary modulators comprising the essential macronutrients at different ratios and a controlled balanced dietary modulator. We assessed, in healthy adult mice, the short-term effects of these modulators when consumed shortly prior to tests with different cognitive and physical demands. A high-fat dietary modulator sustained increased motivation compared to a carbohydrate-rich dietary modulator (p = 0.041) which had a diminishing effect on motivation (p = 0.018). In contrast, a high-carbohydrate modulator had an initial beneficial effect on cognitive flexibility (p = 0.031). No apparent effects of any of the dietary modulators were observed on physical exercise. There is increasing public demand for acute cognitive and motor function enhancers that can improve mental and intellectual performance in daily life, such as in the workplace, studies, or sports activities. Our findings suggest such enhancers should be tailored to the cognitive demand of the task undertaken, as different dietary modulators will have distinct effects when consumed shortly prior to the task.

Hypothalamic deep brain stimulation as a strategy to manage anxiety disorders.

Fear is essential for survival, but excessive anxiety behavior is debilitating. Anxiety disorders affecting millions of people are a global health problem, where new therapies and targets are much needed. Deep brain stimulation (DBS) is established as a therapy in several neurological disorders, but is underexplored in anxiety disorders. The lateral hypothalamus (LH) has been recently revealed as an origin of anxiogenic brain signals, suggesting a target for anxiety treatment. Here, we develop and validate a DBS strategy for modulating anxiety-like symptoms by targeting the LH. We identify a DBS waveform that rapidly inhibits anxiety-implicated LH neural activity and suppresses innate and learned anxiety behaviors in a variety of mouse models. Importantly, we show that the LH DBS displays high temporal and behavioral selectivity: Its affective impact is fast and reversible, with no evidence of side effects such as impaired movement, memory loss, or epileptic seizures. These data suggest that acute hypothalamic DBS could be a useful strategy for managing treatment-resistant anxiety disorders.

Ingested non-essential amino acids recruit brain orexin cells to suppress eating in mice.

Ingested nutrients are proposed to control mammalian behavior by modulating the activity of hypothalamic orexin/hypocretin neurons (HONs). Previous in vitro studies showed that nutrients ubiquitous in mammalian diets, such as non-essential amino acids (AAs) and glucose, modulate HONs in distinct ways. Glucose inhibits HONs, whereas non-essential (but not essential) AAs activate HONs. The latter effect is of particular interest because its purpose is unknown. Here, we show that ingestion of a dietary-relevant mix of non-essential AAs activates HONs and shifts behavior from eating to exploration. These effects persisted despite ablation of a key neural gut → brain communication pathway, the cholecystokinin-sensitive vagal afferents. The behavioral shift induced by the ingested non-essential AAs was recapitulated by targeted HON optostimulation and abolished in mice lacking HONs. Furthermore, lick microstructure analysis indicated that intragastric non-essential AAs and HON optostimulation each reduce the size, but not the frequency, of consumption bouts, thus implicating food palatability modulation as a mechanism for the eating suppression. Collectively, these results suggest that a key purpose of HON activation by ingested, non-essential AAs is to suppress eating and re-initiate food seeking. We propose and discuss possible evolutionary advantages of this, such as optimizing the limited stomach capacity for ingestion of essential nutrients.

Anticipatory countering of motor challenges by premovement activation of orexin neurons.

Countering upcoming challenges with anticipatory movements is a fundamental function of the brain, whose neural implementations remain poorly defined. Recently, premovement neural activation was found outside canonical premotor areas, in the hypothalamic hypocretin/orexin neurons (HONs). The purpose of this hypothalamic activation is unknown. By studying precisely defined mouse-robot interactions, here we show that the premovement HON activity correlates with experience-dependent emergence of anticipatory movements that counter imminent motor challenges. Through targeted, bidirectional optogenetic interference, we demonstrate that the premovement HON activation governs the anticipatory movements. These findings advance our understanding of the behavioral and cognitive impact of temporally defined HON signals and may provide important insights into healthy adaptive movements.

Optogenetic activation of striatal D1R and D2R cells differentially engages downstream connected areas beyond the basal ganglia.

The basal ganglia (BG) are a group of subcortical nuclei responsible for motor and executive function. Central to BG function are striatal cells expressing D1 (D1R) and D2 (D2R) dopamine receptors. D1R and D2R cells are considered functional antagonists that facilitate voluntary movements and inhibit competing motor patterns, respectively. However, whether they maintain a uniform function across the striatum and what influence they exert outside the BG is unclear. Here, we address these questions by combining optogenetic activation of D1R and D2R cells in the mouse ventrolateral caudoputamen with fMRI. Striatal D1R/D2R stimulation evokes distinct activity within the BG-thalamocortical network and differentially engages cerebellar and prefrontal regions. Computational modeling of effective connectivity confirms that changes in D1R/D2R output drive functional relationships between these regions. Our results suggest a complex functional organization of striatal D1R/D2R cells and hint toward an interconnected fronto-BG-cerebellar network modulated by striatal D1R and D2R cells.

Do orexin/hypocretin neurons signal stress or reward?

Hypothalamic neurons that produce the peptide transmitters orexins/hypocretins (HONs) broadcast their predominantly neuroexcitatory outputs to the entire brain via their extremely wide axonal projections. HONs were originally reported to be activated by food deprivation, and to stimulate arousal, energy expenditure, and eating. This led to extensive studies of HONs in the context of nutrient-sensing and energy balance control. While activation of HONs by body energy depletion continues to be supported by experimental evidence, it has also become clear that HONs are robustly activated not only by nutrient depletion, but also by diverse sensory stimuli (both neutral and those associated with rewarding or aversive events), seemingly unrelated to each other or to energy balance. One theory that could unify these findings is that all these stimuli signal "stress" - defined either as a potentially harmful state, or an awareness of reward deficiency. If HON activity is conceptualized as a cumulative representation of stress, then many of the reported HONs outputs - including EEG arousal, sympathetic activation, place avoidance, and exploratory behaviours - could be viewed as logical stress-counteracting responses. We discuss evidence for and against this unifying theory of HON function, including the alterations in HON activity observed in anxiety and depression disorders. We propose that, in order to orchestrate stress-countering responses, HONs need to coactivate motivation and aversion brain systems, and the impact of HON stimulation on affective states may be perceived as rewarding or aversive depending on the baseline HON activity.

Understanding the Link Between Maternal Overnutrition, Cardio-Metabolic Dysfunction and Cognitive Aging.

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?

Control of fear extinction by hypothalamic melanin-concentrating hormone-expressing neurons.

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.

The hypothalamus as a primary coordinator of memory updating.

In the brain, long-term memories correspond to changes in synaptic weights after certain patterns of neural activity. Behaviourally, this corresponds to a change in action evoked by a repeating experience. Forming and updating memories (learning, remembering, forgetting) is fundamental for most aspects of cognitive and motor performance. The roles of the cortex, hippocampus, and amygdala have been studied extensively in this context. However, the lateral hypothalamus - a brain-wide projecting region traditionally known as a nutrient-sensor and controller of arousal and motivation - is also critical for updating many types of associative and non-associative memories. Does the hypothalamus play a primary role in learning, or are hypothalamic effects on learning secondary to changes in brain state such as attention/motivation? We argue that such primary and secondary effects are distinguishable under experimental conditions where attention/motivation states are constant or absent, e.g. during sleep or in reduced in vitro preparations. The documented control by hypothalamus-unique transmitters, such as orexin and MCH, of synaptic strength in isolated brain slice preparations implies a primary role for the hypothalamus in synaptic weight updating, rather than a secondary role due to changes in arousal/attention/motivation states (which are absent in brain slices). Such hypothalamic control of memory-related synaptic machinery may enable gating/thresholding/permissive/tagging operations within yet poorly defined logic gates for memory updating. Hypothalamic signals may thus facilitate cost-benefit analysis of learning and memory in real-world settings. Whether the hypothalamus controls only specific types of learning, or broadcasts a global signal for memory updating, remains to be elucidated.

Maternal overnutrition during critical developmental periods leads to different health adversities in the offspring: relevance of obesity, addiction and schizophrenia.

Maternal overnutrition during sensitive periods of early development increases the risk for obesity and neuropsychiatric disorders later in life. However, it still remains unclear during which phases of early development the offspring is more vulnerable. Here, we investigate the effects of maternal high-fat diet (MHFD) at different stages of pre- or postnatal development and characterize the behavioral, neurochemical and metabolic phenotypes. We observe that MHFD exposure at pre-conception has no deleterious effects on the behavioral and metabolic state of the offspring. Late gestational HFD exposure leads to more prominent addictive-like behaviors with reduced striatal dopamine levels compared to early gestational HFD. Conversely, offspring exposed to MHFD during lactation display the metabolic syndrome and schizophrenia-like phenotype. The latter, is manifested by impaired sensory motor gating, and latent inhibition as well as enhanced sensitivity to amphetamine. These effects are accompanied by higher striatal dopamine levels. Together, our data suggest that MHFD exposure during specific stages of development leads to distinct neuropathological alterations that determine the severity and nature of poor health outcome in adulthood, which may provide insight in identifying effective strategies for early intervention.

Hypothalamic Heuristics for Survival.

Hypothalamic neurons implicated in energy homeostasis (Agrp, POMC, orexin, MCH) display fast, nutrient-independent dynamics. They do not simply mirror the slowly changing internal nutrient levels, but adapt rapidly to diverse external cues. Moreover, instead of eating, neonatal Agrp cells stimulate mother-attracting vocalisations, illustrating heuristic energy control beyond nutrient sensing or dietary self-control.

Environmental and Nutritional Effects Regulating Adipose Tissue Function and Metabolism Across Generations.

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.

Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs.

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.

Maternal overnutrition leads to cognitive and neurochemical abnormalities in C57BL/6 mice.

Objectives: Epidemiological studies have linked maternal obesity with metabolic as well as psychiatric disorders in the progeny. However, very little is known how maternal overnutrition may affect the cognitive abilities of the offspring. Methods: Here, we tested the hypothesis whether maternal high-fat diet (HFD) exposure in mice may induce long-term cognitive impairments and neurochemical dysfunctions in the offspring during different age trajectories. Results: We found that maternal HFD led to cognitive disabilities in adult offspring compared to controls. It was mostly evident in a reference memory and in an associative learning paradigm. More severe and pervasive impairments were evident in the aged adult group across multiple cognitive domains. In addition, adult and aged adult HFD offspring showed potentiation of prepulse inhibition. The cognitive impairments observed at adulthood were associated with attenuations of amino acid levels in the medial prefrontal cortex and the hippocampus regions. Discussion: Our results suggest that HFD offspring are at an increased risk to develop cognitive deficits, affecting learning and memory processes in adulthood. Furthermore, maternal HFD exposure may facilitate or even drive pathological brain aging mainly in the hippocampal and prefrontal cortex structures that may explain the cognitive deficits observed in the offspring.