Infant gut microbiome composition is associated with non-social fear behavior in a pilot study

Experimental manipulation of gut microbes in animal models alters fear behavior and relevant neurocircuitry. In humans, the first year of life is a key period for brain development, the emergence of fearfulness, and the establishment of the gut microbiome. Variation in the infant gut microbiome has previously been linked to cognitive development, but its relationship with fear behavior and neurocircuitry is unknown. In this pilot study of 34 infants, we find that 1-year gut microbiome composition (Weighted Unifrac; lower abundance of Bacteroides, increased abundance of Veillonella, Dialister, and Clostridiales) is significantly associated with increased fear behavior during a non-social fear paradigm. Infants with increased richness and reduced evenness of the 1-month microbiome also display increased non-social fear. This study indicates associations of the human infant gut microbiome with fear behavior and possible relationships with fear-related brain structures on the basis of a small cohort. As such, it represents an important step in understanding the role of the gut microbiome in the development of human fear behaviors, but requires further validation with a larger number of participants.

Midbrain dopaminergic inputs gate amygdala intercalated cell clusters by distinct and cooperative mechanisms in male mice

Dopaminergic signaling plays an important role in associative learning, including fear and extinction learning. Dopaminergic midbrain neurons encode prediction error-like signals when threats differ from expectations. Within the amygdala, GABAergic intercalated cell (ITC) clusters receive one of the densest dopaminergic projections, but their physiological consequences are incompletely understood. ITCs are important for fear extinction, a function thought to be supported by activation of ventromedial ITCs that inhibit central amygdala fear output. In mice, we reveal two distinct novel mechanisms by which mesencephalic dopaminergic afferents control ITCs. Firstly, they co-release GABA to mediate rapid, direct inhibition. Secondly, dopamine suppresses inhibitory interactions between distinct ITC clusters via presynaptic D1 receptors. Early extinction training augments both GABA co-release onto dorsomedial ITCs and dopamine-mediated suppression of dorso- to ventromedial inhibition between ITC clusters. These findings provide novel insights into dopaminergic mechanisms shaping the activity balance between distinct ITC clusters that could support their opposing roles in fear behavior.

Prefrontal Disinhibition in Social Fear: A Vital Action of Somatostatin Interneurons

Social fear and avoidance of social partners and social situations represent the core behavioral symptom of Social Anxiety Disorder (SAD), a prevalent psychiatric disorder worldwide. The pathological mechanism of SAD remains elusive and there are no specific and satisfactory therapeutic options currently available. With the development of appropriate animal models, growing studies start to unravel neuronal circuit mechanisms underlying social fear, and underscore a fundamental role of the prefrontal cortex (PFC). Prefrontal cortical functions are implemented by a finely wired microcircuit composed of excitatory principal neurons (PNs) and diverse subtypes of inhibitory interneurons (INs). Disinhibition, defined as a break in inhibition via interactions between IN subtypes that enhances the output of excitatory PNs, has recently been discovered to serve as an efficient strategy in cortical information processing. Here, we review the rodent animal models of social fear, the prefrontal IN diversity, and their circuits with a particular emphasis on a novel disinhibitory microcircuit mediated by somatostatin-expressing INs in gating social fear behavior. The INs subtype distinct and microcircuit-based mechanism advances our understanding of the etiology of social fear and sheds light on developing future treatment of neuropsychiatric disorders associated with social fear.

Psychological and Physiological Stress in Hens With Bone Damage

Abnormalities in bone development in humans and non-humans can lead to impaired physical and psychological health; however, evidence is lacking regarding the role of individual psychosocial factors in the development of poor bone conditions. Addressing this lack of knowledge, we used low-productive laying hens (n = 93) and assessed behavioral responses to an open-field test [at 17, 18, 29, 33 weeks of age (wa)], an aerial predator test (at 39 wa), and a social reinstatement test (at 42 wa). Bone condition was assessed using a palpation technique on five occasions (at 16, 29, 33, 45, 58 wa), with half of the hens experiencing damage (deviations, fractures, or both) at 29 wa and all hens by 58 wa. Corticosterone (CORT) concentration in feathers (at 16, 33, 58 wa) and body weight (at 23, 47, 58 wa) were also investigated. We hypothesized that lighter birds (at 23 wa) with higher CORT (at 16 wa) and open field-induced fear collected before the onset of lay (at 17 and 18 wa) are associated with a worse bone condition when in lay. We also hypothesized that those birds with more damage at the peak of laying (at 29 wa) would be lighter at 47 and 58 wa and more fearful by showing higher open field-induced (at 29 and 33 wa) and predator-induced fear responses, however, acting less socially toward conspecifics. These hens were also expected to have higher CORT (at 33 and 58 wa). Our results show no association between open-field fear level and fear behavior, CORT concentration, or body weight on the one hand (all measured before starting to lay) and bone damage at 29 wa on the other. When in lay, bone damage was associated with more pecking and less crossing zones when faced with an open-field situation at 29 wa and improved sociality at 42 wa. This study provides the first evidence of a relationship of bone health with fear, sociality, and stress response. When in poor bone condition, our hens had enhanced psychological stress measured by fear behavior reactivity but not physiological stress measured as feather CORT concentration.

Midbrain dopaminergic inputs gate amygdala intercalated cell clusters by distinct and cooperative mechanisms

Dopaminergic signaling plays an important role in associative learning including fear and extinction learning. Dopaminergic midbrain neurons encode prediction error-like signals when threats differ from expectations. Within the amygdala, GABAergic intercalated cell (ITC) clusters receive the densest dopaminergic projections, but their physiological consequences are incompletely understood. ITCs are important for fear extinction, a function thought to be supported by activation of ventromedial cluster ITCs that inhibit central amygdala fear output. In mice, we reveal two distinct mechanisms how mesencephalic dopaminergic afferents control ITCs. Firstly, they co-release GABA to mediate rapid, direct inhibition. Secondly, dopamine suppresses inhibitory interactions between distinct ITC clusters via presynaptic D1-receptors. Early extinction training augments both, GABA co-release onto dorso-medial ITCs and dopamine-mediated suppression of dorso- to ventromedial inhibition between ITC clusters. These findings provide novel insights into dopaminergic mechanisms shaping the activity balance between distinct ITC clusters that could support their opposing roles in fear behavior.

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.