The effect of acute social isolation on neural molecular responses in components of the social decision-making network.

Prolonged or chronic social isolation has pronounced effects on animals, ranging from altered stress responses, increased anxiety and aggressive behaviour, and even increased mortality. The effects of shorter periods of isolation are much less well researched; however, short periods of isolation are used routinely for testing animal behaviour and physiology. Here, we studied how a 3 h period of isolation from a cagemate affected neural gene expression in three brain regions that contain important components of the social decision-making network, the hypothalamus, the nucleus taeniae of the amygdala, and the bed nucleus of the stria terminalis, using a gregarious bird as a model (zebra finches). We found evidence suggestive of altered neural activity, synaptic transmission, metabolism, and even potentially pain perception, all of which could create cofounding effects on experimental tests that involve isolating animals. We recommend that the effects of short-term social isolation need to be better understood and propose alternatives to isolating animals for testing.

Convergent direct and indirect cortical streams shape avoidance decisions in mice via the midline thalamus.

Current concepts of corticothalamic organization in the mammalian brain are mainly based on sensory systems, with less focus on circuits for higher-order cognitive functions. In sensory systems, first-order thalamic relays are driven by subcortical inputs and modulated by cortical feedback, while higher-order relays receive strong excitatory cortical inputs. The applicability of these principles beyond sensory systems is uncertain. We investigated mouse prefronto-thalamic projections to the midline thalamus, revealing distinct top-down control. Unlike sensory systems, this pathway relies on indirect modulation via the thalamic reticular nucleus (TRN). Specifically, the prelimbic area, which influences emotional and motivated behaviors, impacts instrumental avoidance responses through direct and indirect projections to the paraventricular thalamus. Both pathways promote defensive states, but the indirect pathway via the TRN is essential for organizing avoidance decisions through disinhibition. Our findings highlight intra-thalamic circuit dynamics that integrate cortical cognitive signals and their role in shaping complex behaviors.

A parabrachial hub for the prioritization of survival behavior.

Long-term sustained pain in the absence of acute physical injury is a prominent feature of chronic pain conditions. While neurons responding to noxious stimuli have been identified, understanding the signals that persist without ongoing painful stimuli remains a challenge. Using an ethological approach based on the prioritization of adaptive survival behaviors, we determined that neuropeptide Y (NPY) signaling from multiple sources converges on parabrachial neurons expressing the NPY Y1 receptor to reduce sustained pain responses. Neural activity recordings and computational modeling demonstrate that activity in Y1R parabrachial neurons is elevated following injury, predicts functional coping behavior, and is inhibited by competing survival needs. Taken together, our findings suggest that parabrachial Y1 receptor-expressing neurons are a critical hub for endogenous analgesic pathways that suppress sustained pain states.

Divergent projections of the paraventricular nucleus of the thalamus mediate the selection of passive and active defensive behaviors.

The appropriate selection of passive and active defensive behaviors in threatening situations is essential for survival. Previous studies have shown that passive defensive responses depend on activity of the central nucleus of the amygdala (CeA), whereas active ones primarily rely on the nucleus accumbens (NAc). However, the mechanisms underlying flexible switching between these two types of responses remain unknown. Here we show in mice that the paraventricular thalamus (PVT) mediates the selection of defensive behaviors through its interaction with the CeA and the NAc. We show that the PVT-CeA pathway drives conditioned freezing responses, whereas the PVT-NAc pathway is inhibited during freezing and, instead, signals active avoidance events. Optogenetic manipulations revealed that activity in the PVT-CeA or PVT-NAc pathway biases behavior toward the selection of passive or active defensive responses, respectively. These findings provide evidence that the PVT mediates flexible switching between opposing defensive behaviors.

A ventrolateral medulla-midline thalamic circuit for hypoglycemic feeding.

Marked deficits in glucose availability, or glucoprivation, elicit organism-wide counter-regulatory responses whose purpose is to restore glucose homeostasis. However, while catecholamine neurons of the ventrolateral medulla (VLMCA) are thought to orchestrate these responses, the circuit and cellular mechanisms underlying specific counter-regulatory responses are largely unknown. Here, we combined anatomical, imaging, optogenetic and behavioral approaches to interrogate the circuit mechanisms by which VLMCA neurons orchestrate glucoprivation-induced food seeking behavior. Using these approaches, we found that VLMCA neurons form functional connections with nucleus accumbens (NAc)-projecting neurons of the posterior portion of the paraventricular nucleus of the thalamus (pPVT). Importantly, optogenetic manipulations revealed that while activation of VLMCA projections to the pPVT was sufficient to elicit robust feeding behavior in well fed mice, inhibition of VLMCA-pPVT communication significantly impaired glucoprivation-induced feeding while leaving other major counterregulatory responses intact. Collectively our findings identify the VLMCA-pPVT-NAc pathway as a previously-neglected node selectively controlling glucoprivation-induced food seeking. Moreover, by identifying the ventrolateral medulla as a direct source of metabolic information to the midline thalamus, our results support a growing body of literature on the role of the PVT in homeostatic regulation.

Immune-Endocrine Links to Gregariousness in Wild House Mice.

Social interactions are critically important for survival and impact overall-health, but also impose costs on animals, such as exposure to contagious agents. The immune system can play a critical role in modulating social behavior when animals are sick, as has been demonstrated within the context of "sickness behaviors." Can immune molecules affect or be affected by social interactions even when animals are not sick, therefore serving a role in mediating pathogen exposure? We tested whether markers of immune function in both the blood and the brain are associated with gregariousness, quantified as number of animals interacted with per day. To do this, we used remote tracking of social interactions of a wild population of house mice (Mus musculus domesticus) to categorize animals in terms of gregariousness. Blood, hair, brain and other tissue samples from animals with extreme gregariousness phenotypes were collected. We then tested whether the levels of three important cytokines (TNF-α, IFN-γ and IL-1ß) in the serum, cortex and hypothalamus of these animals could be explained by the gregariousness phenotype and/or sex of the mice. Using the hair as a long-term quantification of steroid hormones, we also tested whether corticosterone, progesterone and testosterone differed by social phenotype. We found main effects of gregariousness and sex on the serum levels of TNF-α, but not on IFN-γ or IL-1ß. Brain gene expression levels were not different between phenotypes. All hair steroids tended to be elevated in animals of high gregariousness phenotype, independent of sex. In sum, elements of the immune system may be associated with gregariousness, even outside of major disease events. These results extend our knowledge of the role that immune signals have in contributing to the regulation of social behaviors outside periods of illness.