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Neurotransmitters and neuromodulators have a wide range of key roles throughout the nervous system. However, their dynamics in both health and disease have been challenging to assess, owing to the lack of in vivo tools to track them with high spatiotemporal resolution. Thus, developing a platform that enables minimally invasive, large-scale and long-term monitoring of neurotransmitters and neuromodulators with high sensitivity, high molecular specificity and high spatiotemporal resolution has been essential. Here, we review the methods available for monitoring the dynamics of neurotransmitters and neuromodulators. Following a brief summary of non-genetically encoded methods, we focus on recent developments in genetically encoded fluorescent indicators, highlighting how these novel indicators have facilitated advances in our understanding of the functional roles of neurotransmitters and neuromodulators in the nervous system. These studies present a promising outlook for the future development and use of tools to monitor neurotransmitters and neuromodulators.The levels of neurotransmitters and neuromodulators have been difficult to track. In this Review, Wu et al. give an overview of conventional and modern tools and imaging methods for monitoring neurochemicals, with a focus on genetically encoded sensors.

Aggression is a social behavior essential for securing resources and defending oneself and family. Thanks to its indispensable function in competition and thus survival, aggression exists widely across animal species, including humans. Classical works from Tinbergen and Lorenz concluded that instinctive behaviors including aggression are mediated by hardwired brain circuitries that specialize in processing certain sensory inputs to trigger stereotyped motor outputs. They further suggest that instinctive behaviors are influenced by an animal’s internal state and past experiences. Following this conceptual framework, here we review our current understanding regarding the neural substrates underlying aggression generation, highlighting an evolutionarily conserved ‘core aggression circuit’ composed of four subcortical regions. We further discuss the neural mechanisms that support changes in aggression based on the animal’s internal state. We aim to provide an overview of features of aggression and the relevant neural substrates across species, highlighting findings in rodents, primates and songbirds.Aggression is an instinctive behavior supported by hardwired neural circuits. Julieta Lischinsky and Dayu Lin review our current understanding of the neural circuits of aggression across species and their modulation by internal state.

Corticotropin-releasing factor (CRF) that is released from the paraventricular nucleus (PVN) of the hypothalamus is essential for mediating stress response by activating the hypothalamic–pituitary–adrenal axis. CRF-releasing PVN neurons receive inputs from multiple brain regions that convey stressful events, but their neuronal dynamics on the timescale of behavior remain unknown. Here, our recordings of PVN CRF neuronal activity in freely behaving mice revealed that CRF neurons are activated immediately by a range of aversive stimuli. By contrast, CRF neuronal activity starts to drop within a second of exposure to appetitive stimuli. Optogenetic activation or inhibition of PVN CRF neurons was sufficient to induce a conditioned place aversion or preference, respectively. Furthermore, conditioned place aversion or preference induced by natural stimuli was significantly decreased by manipulating PVN CRF neuronal activity. Together, these findings suggest that the rapid, biphasic responses of PVN CRF neurons encode the positive and negative valences of stimuli.Animals must determine quickly whether any given environmental stimuli are beneficial or detrimental. This work reveals a novel strategy to encode opposing valences by a single population of CRF neurons in the hypothalamus.

Sexual and aggressive behaviors are fundamental to animal survival and reproduction. The medial preoptic nucleus (MPN) and ventrolateral part of the ventromedial hypothalamus (VMHvl) are essential regions for male sexual and aggressive behaviors, respectively. While key inhibitory inputs to the VMHvl and MPN have been identified, the extrahypothalamic excitatory inputs essential for social behaviors remain elusive. Here we identify estrogen receptor alpha (Esr1)-expressing cells in the posterior amygdala (PA) as a main source of excitatory inputs to the hypothalamus and key mediators for mating and fighting in male mice. We find two largely distinct PA subpopulations that differ in connectivity, gene expression, in vivo responses and social behavior relevance. MPN-projecting PAEsr1+ cells are activated during mating and are necessary and sufficient for male sexual behaviors, while VMHvl-projecting PAEsr1+ cells are excited during intermale aggression and promote attacks. These findings place the PA as a key node in both male aggression and reproduction circuits.Yamaguchi et al. identify a little-known amygdalar region, the posterior amygdala, as a key node in male mouse social behaviors. Two largely non-overlapping subpopulations in the posterior amygdala form parallel projections to distinct hypothalamic regions to regulate mating and fighting.

The authors show that the ventrolateral aspect of the ventromedial hypothalamus (VMHvl), a region previously implicated in attack behavior, can also drive flexible aggression-seeking behavior. When male mice learn a task to seek out attack opportunities, activity in the VMHvl tracks and bidirectionally modulates the seeking behavior that leads to future attack. In many vertebrate species, certain individuals will seek out opportunities for aggression, even in the absence of threat-provoking cues. Although several brain areas have been implicated in the generation of attack in response to social threat, little is known about the neural mechanisms that promote self-initiated or 'voluntary' aggression-seeking when no threat is present. To explore this directly, we utilized an aggression-seeking task in which male mice self-initiated aggression trials to gain brief and repeated access to a weaker male that they could attack. In males that exhibited rapid task learning, we found that the ventrolateral part of the ventromedial hypothalamus (VMHvl), an area with a known role in attack, was essential for aggression-seeking. Using both single-unit electrophysiology and population optical recording, we found that VMHvl neurons became active during aggression-seeking and that their activity tracked changes in task learning and extinction. Inactivation of the VMHvl reduced aggression-seeking behavior, whereas optogenetic stimulation of the VMHvl accelerated moment-to-moment aggression-seeking and intensified future attack. These data demonstrate that the VMHvl can mediate both acute attack and flexible seeking actions that precede attack.

To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks 1 . Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOR OXT ) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvl OXTR ) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvl OXTR cells minimally respond to aggressor cues. During defeat, aVMHvl OXTR cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvl OXTR cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity. In mice, the neural mechanisms underlying aversive social learning, specifically avoidance and fear after defeat, involve oxytocin signalling in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part.

Electrical stimulation of certain hypothalamic regions in cats and rodents can elicit attack behaviour, but the exact location of relevant cells within these regions, their requirement for naturally occurring aggression and their relationship to mating circuits have not been clear. Genetic methods for neural circuit manipulation in mice provide a potentially powerful approach to this problem, but brain-stimulation-evoked aggression has never been demonstrated in this species. Here we show that optogenetic, but not electrical, stimulation of neurons in the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) causes male mice to attack both females and inanimate objects, as well as males. Pharmacogenetic silencing of VMHvl reversibly inhibits inter-male aggression. Immediate early gene analysis and single unit recordings from VMHvl during social interactions reveal overlapping but distinct neuronal subpopulations involved in fighting and mating. Neurons activated during attack are inhibited during mating, suggesting a potential neural substrate for competition between these opponent social behaviours. Possible link between aggression and mating behaviour Certain regions of the hypothalamus are known to be important in aggression. Until recently, it has not been possible to learn much more than that because it was difficult to stimulate specific cell types within a mixed population of cells. David Anderson and colleagues have used optogenetics to solve this specificity problem, and find that optogenetic stimulation of neurons in a subdivision within the ventromedial hypothalamus can elicit inappropriate attack behaviours — but that electrical stimulation does not produce the same result. Additional analysis of genetic and electrophysiological activity revealed overlapping neuronal subpopulations involved in fighting and mating, with potential competition between these behaviours, as neurons activated during aggression are inhibited during mating. Certain regions of the hypothalamus are important in aggression, but until recently, it has been difficult to specifically stimulate specific cell types within a mixed population of cells. Here, optogenetics is used to solve this specificity problem, finding that optogenetic stimulation of a subdivision within the ventromedial hypothalamus can elicit inappropriate attack behaviours in mice, but electrical stimulation does not produce the same result. Additional analysis of genetic and electrophysiological activity revealed overlapping neuronal subpopulations involved in fighting and mating, with potential competition between these behaviours, as neurons activated during aggression are inhibited during mating.

Social behaviors are innate and supported by dedicated neural circuits, but the molecular identities of these circuits and how they are established developmentally and shaped by experience remain unclear. Here we show that medial amygdala (MeA) cells originating from two embryonically parcellated developmental lineages have distinct response patterns and functions in social behavior in male mice. MeA cells expressing the transcription factor Foxp2 (MeA Foxp2 ) are specialized for processing male conspecific cues and are essential for adult inter-male aggression. By contrast, MeA cells derived from the Dbx1 lineage (MeA Dbx1 ) respond broadly to social cues, respond strongly during ejaculation and are not essential for male aggression. Furthermore, MeA Foxp2 and MeA Dbx1 cells show differential anatomical and functional connectivity. Altogether, our results suggest a developmentally hardwired aggression circuit at the MeA level and a lineage-based circuit organization by which a cell’s embryonic transcription factor profile determines its social information representation and behavioral relevance during adulthood. The authors describe the connectivity, response profile and behavioral roles of two transcriptionally defined amygdala populations from separate embryonic lineages and show how responses of one population change with social experience.

Dopamine (DA) plays a critical role in the brain, and the ability to directly measure dopaminergic activity is essential for understanding its physiological functions. We therefore developed red fluorescent G-protein-coupled receptor-activation-based DA (GRAB DA ) sensors and optimized versions of green fluorescent GRAB DA sensors. In response to extracellular DA, both the red and green GRAB DA sensors exhibit a large increase in fluorescence, with subcellular resolution, subsecond kinetics and nanomolar-to-submicromolar affinity. Moreover, the GRAB DA sensors resolve evoked DA release in mouse brain slices, detect evoked compartmental DA release from a single neuron in live flies and report optogenetically elicited nigrostriatal DA release as well as mesoaccumbens dopaminergic activity during sexual behavior in freely behaving mice. Coexpressing red GRAB DA with either green GRAB DA or the calcium indicator GCaMP6s allows tracking of dopaminergic signaling and neuronal activity in distinct circuits in vivo. Red and improved green versions of the genetically encoded dopamine sensor GRAB DA have been developed. These neurotransmitter sensors are used alone or in combination with, for example, calcium sensors in behaving fruit flies and rodents.

Psychological stress can trigger physiological responses, including an increase in body temperature. A neural circuit that underlies this stress-induced heat response has been identified. A neuronal pathway that governs stress-induced hyperthermia.