Social buffering in rats reduces fear by oxytocin triggering sustained changes in central amygdala neuronal activity.

The presence of a companion can reduce fear, but the neural mechanisms underlying this social buffering of fear are incompletely known. We studied social buffering of fear in male and female, and its encoding in the amygdala of male, auditory fear-conditioned rats. Pharmacological, opto,- and/or chemogenetic interventions showed that oxytocin signaling from hypothalamus-to-central amygdala projections underlied fear reduction acutely with a companion and social buffering retention 24 h later without a companion. Single-unit recordings with optetrodes in the central amygdala revealed fear-encoding neurons (showing increased conditioned stimulus-responses after fear conditioning) inhibited by social buffering and blue light-stimulated oxytocinergic hypothalamic projections. Other central amygdala neurons showed baseline activity enhanced by blue light and companion exposure, with increased conditioned stimulus responses that persisted without the companion. Social buffering of fear thus switches the conditioned stimulus from encoding "fear" to "safety" by oxytocin-mediated recruitment of a distinct group of central amygdala "buffer neurons".

ASIC1a affects hypothalamic signaling and regulates the daily rhythm of body temperature in mice.

The body temperature of mice is higher at night than during the day. We show here that global deletion of acid-sensing ion channel 1a (ASIC1a) results in lower body temperature during a part of the night. ASICs are pH sensors that modulate neuronal activity. The deletion of ASIC1a decreased the voluntary activity at night of mice that had access to a running wheel but did not affect their spontaneous activity. Daily rhythms of thyrotropin-releasing hormone mRNA in the hypothalamus and of thyroid-stimulating hormone ß mRNA in the pituitary, and of prolactin mRNA in the hypothalamus and pituitary were suppressed in ASIC1a-/- mice. The serum thyroid hormone levels were however not significantly changed by ASIC1a deletion. Our findings indicate that ASIC1a regulates activity and signaling in the hypothalamus and pituitary. This likely leads to the observed changes in body temperature by affecting the metabolism or energy expenditure.

A genetically encoded sensor measures temporal oxytocin release from different neuronal compartments.

Oxytocin (OT), a peptide hormone and neuromodulator, is involved in diverse physiological and pathophysiological processes in the central nervous system and the periphery. However, the regulation and functional sequences of spatial OT release in the brain remain poorly understood. We describe a genetically encoded G-protein-coupled receptor activation-based (GRAB) OT sensor called GRABOT1.0. In contrast to previous methods, GRABOT1.0 enables imaging of OT release ex vivo and in vivo with suitable sensitivity, specificity and spatiotemporal resolution. Using this sensor, we visualize stimulation-induced OT release from specific neuronal compartments in mouse brain slices and discover that N-type calcium channels predominantly mediate axonal OT release, whereas L-type calcium channels mediate somatodendritic OT release. We identify differences in the fusion machinery of OT release for axon terminals versus somata and dendrites. Finally, we measure OT dynamics in various brain regions in mice during male courtship behavior. Thus, GRABOT1.0 provides insights into the role of compartmental OT release in physiological and behavioral functions.

The interplay of hypoxic and mental stress: Implications for anxiety and depressive disorders.

Adequate oxygen supply is essential for the human brain to meet its high energy demands. Therefore, elaborate molecular and systemic mechanism are in place to enable adaptation to low oxygen availability. Anxiety and depressive disorders are characterized by alterations in brain oxygen metabolism and of its components, such as mitochondria or hypoxia inducible factor (HIF)-pathways. Conversely, sensitivity and tolerance to hypoxia may depend on parameters of mental stress and the severity of anxiety and depressive disorders. Here we discuss relevant mechanisms of adaptations to hypoxia, as well as their involvement in mental stress and the etiopathogenesis of anxiety and depressive disorders. We suggest that mechanisms of adaptations to hypoxia (including metabolic responses, inflammation, and the activation of chemosensitive brain regions) modulate and are modulated by stress-related pathways and associated psychiatric diseases. While severe chronic hypoxia or dysfunctional hypoxia adaptations can contribute to the pathogenesis of anxiety and depressive disorders, harnessing controlled responses to hypoxia to increase cellular and psychological resilience emerges as a novel treatment strategy for these diseases.

The petting factor: Oxytocin and social touch.

In this issue of Neuron, Yu et al. (2022) uncovered a sensory pathway by which social touch can activate oxytocin neurons in the hypothalamus. Their stimulation protocol could deliver pleasant sensory stimuli to juvenile mice, increasing their later-life social interactions.

Astrocytes mediate the effect of oxytocin in the central amygdala on neuronal activity and affective states in rodents.

Oxytocin (OT) orchestrates social and emotional behaviors through modulation of neural circuits. In the central amygdala, the release of OT modulates inhibitory circuits and, thereby, suppresses fear responses and decreases anxiety levels. Using astrocyte-specific gain and loss of function and pharmacological approaches, we demonstrate that a morphologically distinct subpopulation of astrocytes expresses OT receptors and mediates anxiolytic and positive reinforcement effects of OT in the central amygdala of mice and rats. The involvement of astrocytes in OT signaling challenges the long-held dogma that OT acts exclusively on neurons and highlights astrocytes as essential components for modulation of emotional states under normal and chronic pain conditions.

Early Secure Attachment as a Protective Factor Against Later Cognitive Decline and Dementia.

The etiology of neurodegenerative disorders such as dementia is complex and incompletely understood. Interest in a developmental perspective to these pathologies is gaining momentum. An early supportive social environment seems to have important implications for social, affective and cognitive abilities across the lifespan. Attachment theory may help to explain the link between these early experiences and later outcomes. This theory considers early interactions between an infant and its caregiver to be crucial to shaping social behavior and emotion regulation strategies throughout adult life. Furthermore, research has demonstrated that such early attachment experiences can, potentially through epigenetic mechanisms, have profound neurobiological and cognitive consequences. Here we discuss how early attachment might influence the development of affective, cognitive, and neurobiological resources that could protect against cognitive decline and dementia. We argue that social relations, both early and late in life, are vital to ensuring cognitive and neurobiological health. The concepts of brain and cognitive reserve are crucial to understanding how environmental factors may impact cognitive decline. We examine the role that attachment might play in fostering brain and cognitive reserve in old age. Finally, we put forward the concept of affective reserve, to more directly frame the socio-affective consequences of early attachment as protectors against cognitive decline. We thereby aim to highlight that, in the study of aging, cognitive decline and dementia, it is crucial to consider the role of affective and social factors such as attachment.

Neuropeptide signalling in the central nucleus of the amygdala.

The central amygdala has a rich repertoire of neuropeptides and neuropeptide receptors. The diverse ways in which they modulate neuronal activity and influence synaptic activity are discussed here mostly in the context of fear and anxiety-related behaviour but also with respect to nociception, hunger and satiety and chronic alcohol exposure that often come together with anxiety. It appears that neuropeptides exert rather specific effects on behaviour and physiology that can be quite different from the effects evoked by opto- or chemogenetical stimulation of the central amygdala neurons that synthesise them or express their receptors. Also, neuropeptides might work synergistically or antagonistically to fine-tune the final outcome of sensory processing in the central amygdala and bring about appropriate physiological and behavioural responses to threat. Taken together, we propose that neuropeptide signalling in the central amygdala mainly serves to establish or maintain emotional homeostasis in response to threatening and other sensory stimuli.

Acute and long-lasting effects of oxytocin in cortico-limbic circuits: consequences for fear recall and extinction.

The extinction of conditioned fear responses entrains the formation of safe new memories to decrease those behavioral responses. The knowledge in neuronal mechanisms of extinction is fundamental in the treatment of anxiety and fear disorders. Interestingly, the use of pharmacological compounds that reduce anxiety and fear has been shown as a potent co-adjuvant in extinction therapy. However, the efficiency and mechanisms by which pharmacological compounds promote extinction of fear memories remains still largely unknown and would benefit from a validation based on functional neuronal circuits, and the neurotransmitters that modulate them. From this perspective, oxytocin receptor signaling, which has been shown in cortical and limbic areas to modulate numerous functions (Eliava et al. Neuron 89(6):1291-1304, 2016), among them fear and anxiety circuits, and to enhance the salience of social stimuli (Stoop Neuron 76(1):142-59, 2012), may offer an interesting perspective. Experiments in animals and humans suggest that oxytocin could be a promising pharmacological agent at adjusting memory consolidation to boost fear extinction. Additionally, it is possible that long-term changes in endogenous oxytocin signaling can also play a role in reducing expression of fear at different brain targets. In this review, we summarize the effects reported for oxytocin in cortico-limbic circuits and on fear behavior that are of relevance for the modulation and potential extinction of fear memories.

The Basolateral Amygdala Is Essential for Rapid Escape: A Human and Rodent Study.

Rodent research delineates how the basolateral amygdala (BLA) and central amygdala (CeA) control defensive behaviors, but translation of these findings to humans is needed. Here, we compare humans with natural-selective bilateral BLA lesions to rats with a chemogenetically silenced BLA. We find, across species, an essential role for the BLA in the selection of active escape over passive freezing during exposure to imminent yet escapable threat (Timm). In response to Timm, BLA-damaged humans showed increased startle potentiation and BLA-silenced rats demonstrated increased startle potentiation, freezing, and reduced escape behavior as compared to controls. Neuroimaging in humans suggested that the BLA reduces passive defensive responses by inhibiting the brainstem via the CeA. Indeed, Timm conditioning potentiated BLA projections onto an inhibitory CeA pathway, and pharmacological activation of this pathway rescued deficient Timm responses in BLA-silenced rats. Our data reveal how the BLA, via the CeA, adaptively regulates escape behavior from imminent threat and that this mechanism is evolutionary conserved across rodents and humans.

Interplay between Oxytocin and Sensory Systems in the Orchestration of Socio-Emotional Behaviors.

The neuropeptide oxytocin (OT) attracts the interest of neuroscientists, psychologists, and psychiatrists due to its capacity to modulate emotional and social behavior. Although much has been published on the effects of OT on brain regions and mechanisms at the core of these processes, its role in sensory processing, so important for detecting social context with sufficient accuracy and sensitivity, has been much less studied. In the present review, we summarize evidence for OT modulation of sensory processing and, conversely, effects of sensory input on endogenous OT signaling. We concentrate on mammals, aiming to provide a systematic analysis of the current knowledge on this reciprocal regulation and the role it may play in social and emotional behaviors.

Sniffing and Oxytocin: Effects on Olfactory Memories.

In this issue of Neuron, Oettl et al. (2016) show how oxytocin can boost processing of olfactory information in female rats by a top-downregulation from the anterior olfactory nucleus onto the main olfactory bulb. As a result, interactions with juvenile conspecifics receive more attention and are longer memorized.

A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing.

Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery.

New opportunities in vasopressin and oxytocin research: a perspective from the amygdala.

In the present review, we discuss how the evolution of oxytocin and vasopressin from a single ancestor peptide after gene duplication has stimulated the development of the vertebrate social brain. Separate production sites became possible with a hypothalamic development, which, interestingly, is triggered by the same transcription factors that underlie the development of various subcortical regions where vasopressin and oxytocin receptors are adjacently expressed and which are connected by inhibitory circuits. The opposite modulation of their output by vasopressin and oxytocin could thus create a dynamic equilibrium for rapid responsiveness to external stimuli. At the level of the individual, nurturing early in life can long-lastingly program oxytocin signaling, maintaining a capability of learning and sensitivity to external stimuli that contributes to development of social behavior in adulthood. Oxytocin and vasopressin are thus important for the development of a vertebrate brain that supports bonding between individuals and building of an interactive community.

Neuromodulation by oxytocin and vasopressin in the central nervous system as a basis for their rapid behavioral effects.

The last several years have seen an increasing number of studies that describe effects of oxytocin and vasopressin on the behavior of animals or humans. Studies in humans have reported behavioral changes and, through fMRI, effects on brain function. These studies are paralleled by a large number of reports, mostly in rodents, that have also demonstrated neuromodulatory effects by oxytocin and vasopressin at the circuit level in specific brain regions. It is the scope of this review to give a summary of the most recent neuromodulatory findings in rodents with the aim of providing a potential neurophysiological basis for their behavioral effects. At the same time, these findings may point to promising areas for further translational research towards human applications.

Neuromodulation by oxytocin and vasopressin.

Oxytocin (OT) and vasopressin (VP) are two closely related neuropeptides, widely known for their peripheral hormonal effects. Specific receptors have also been found in the brain, where their neuromodulatory actions have meanwhile been described in a large number of regions. Recently, it has become possible to study their endogenous neuropeptide release with the help of OT/VP promoter-driven expression of fluorescent proteins and light-activated ion channels. In this review, I summarize the neuromodulatory effects of OT and VP in different brain regions by grouping these into different behavioral systems, highlighting their concerted, and at times opposite, effects on different aspects of behavior.

Evoked axonal oxytocin release in the central amygdala attenuates fear response.

The hypothalamic neuropeptide oxytocin (OT), which controls childbirth and lactation, receives increasing attention for its effects on social behaviors, but how it reaches central brain regions is still unclear. Here we gained by recombinant viruses selective genetic access to hypothalamic OT neurons to study their connectivity and control their activity by optogenetic means. We found axons of hypothalamic OT neurons in the majority of forebrain regions, including the central amygdala (CeA), a structure critically involved in OT-mediated fear suppression. In vitro, exposure to blue light of channelrhodopsin-2-expressing OT axons activated a local GABAergic circuit that inhibited neurons in the output region of the CeA. Remarkably, in vivo, local blue-light-induced endogenous OT release robustly decreased freezing responses in fear-conditioned rats. Our results thus show widespread central projections of hypothalamic OT neurons and demonstrate that OT release from local axonal endings can specifically control region-associated behaviors.

Oxytocin selectively gates fear responses through distinct outputs from the central amygdala.

Central amygdala (CeA) projections to hypothalamic and brain stem nuclei regulate the behavioral and physiological expression of fear, but it is unknown whether these different aspects of the fear response can be separately regulated by the CeA. We combined fluorescent retrograde tracing of CeA projections to nuclei that modulate fear-related freezing or cardiovascular responses with in vitro electrophysiological recordings and with in vivo monitoring of related behavioral and physiological parameters. CeA projections emerged from separate neuronal populations with different electrophysiological characteristics and different response properties to oxytocin. In vivo, oxytocin decreased freezing responses in fear-conditioned rats without affecting the cardiovascular response. Thus, neuropeptidergic signaling can modulate the CeA outputs through separate neuronal circuits and thereby individually steer the various aspects of the fear response.

Opposite effects of oxytocin and vasopressin on the emotional expression of the fear response.

Oxytocin and vasopressin are two neuropeptides that have been extensively studied for their systemic and physiological roles. Studies in rodents show that oxytocin and vasopressin play an opposite role in several behavioural and physiological tests for anxiety and fear. Their effects on single cell activity in the central amygdala (CeA) triggered a number of electrophysiological studies that allowed us to develop a model of their opposing effects. In our model, GABAergic neurons in the lateral part of the central amygdala are excited by oxytocin and project to the medial part where they inhibit neurons that can be excited by vasopressin. Besides oxytocin and vasopressin, the CeA expresses a large number of other neuropeptide receptors and the question arises if a similar model can apply to their actions. We here develop a hypothesis in which neuropeptides, through their effects on distinct populations in the CeA, affect specific projections and specific physiological expressions of the fear response. Our hypothesis may be of importance for the current interest in neuropeptide receptors as therapeutic targets for neuropsychiatric disorders.