SUMMARY Deciphering the neural mechanisms of social behavior has propelled the growth of social neuroscience. The exact computations of the social brain, however, remain elusive. Here we investigated how the human brain tracks ongoing changes in social relationships using functional neuroimaging. Participants were lead characters in a role-playing game in which they were to find a new home and a job through interactions with virtual cartoon characters. We found that a two-dimensional geometric model of social relationships, a “social space” framed by power and affiliation, predicted hippocampal activity. Moreover, participants who reported better social skills showed stronger covariance between hippocampal activity and “movement” through “social space.” The results suggest that the hippocampus is crucial for social cognition, and imply that beyond framing physical locations, the hippocampus computes a more general, inclusive, abstract, and multidimensional cognitive map consistent with its role in episodic memory.

Numerous studies have employed repeated social defeat stress (RSDS) to study the neurobiological mechanisms of depression in rodents. An important limitation of RSDS studies to date is that they have been conducted exclusively in male mice due to the difficulty of initiating attack behavior directed toward female mice. Here, we establish a female mouse model of RSDS by inducing male aggression toward females through chemogenetic activation of the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl). We demonstrate that females susceptible to RSDS display social avoidance, anxiety-like behavior, reduction of body weight, and elevated levels of circulating interleukin 6. In contrast, a subset of mice we term resilient only display anxiety-like behaviors after RSDS. This model allows for investigation of sex differences in the neurobiological mechanisms of defeat‒induced depression‒like behaviors. A robust female social defeat model is a critical first step in the identification and development of novel therapeutic compounds to treat depression and anxiety disorders in women.

Numerous studies have found that chronic cocaine increases dendritic spine density of medium spiny neurons in the nucleus accumbens (NAc). Here, we employed single cell microinjections and advanced 3D imaging and analysis techniques to extend these findings in several important ways: by assessing cocaine regulation of dendritic spines in the core versus shell subregions of NAc in the mouse, over a broad time course (4 hours, 24 hours, or 28 days) of withdrawal from chronic cocaine, and with a particular focus on proximal versus distal dendrites. Our data demonstrate subregion-specific, and in some cases opposite, regulation of spines by cocaine on proximal but not distal dendrites. Notably, all observed density changes were attributable to selective regulation of thin spines. At 4 hours post-injection, the proximal spine density is unchanged in the core but significantly increased in the shell. At 24 hours, the density of proximal dendritic spines is reduced in the core but increased in the shell. Such down-regulation of thin spines in the core persists through 28 days of withdrawal, while the spine density in the shell returns to baseline levels. Consistent with previous results, dendritic tips exhibited up-regulation of dendritic spines after 24 hours of withdrawal, an effect localized to the shell. The divergence in regulation of proximal spine density in NAc core versus shell by cocaine correlates with recently reported electrophysiological data from a similar drug administration regimen and might represent a key mediator of changes in the reward circuit that drive aspects of addiction.

The dementia of Alzheimer's disease (AD) results primarily from degeneration of neurons that furnish glutamatergic corticocortical connections that subserve cognition. Although neuron death is minimal in the absence of AD, age-related cognitive decline does occur in animals as well as humans, and it decreases quality of life for elderly people. Age-related cognitive decline has been linked to synapse loss and/or alterations of synaptic proteins that impair function in regions such as the hippocampus and prefrontal cortex. These synaptic alterations are likely reversible, such that maintenance of synaptic health in the face of aging is a critically important therapeutic goal. Here, we show that riluzole can protect against some of the synaptic alterations in hippocampus that are linked to age-related memory loss in rats. Riluzole increases glutamate uptake through glial transporters and is thought to decrease glutamate spillover to extrasynaptic NMDA receptors while increasing synaptic glutamatergic activity. Treated aged rats were protected against age-related cognitive decline displayed in nontreated aged animals. Memory performance correlated with density of thin spines on apical dendrites in CA1, although not with mushroom spines. Furthermore, riluzole-treated rats had an increase in clustering of thin spines that correlated with memory performance and was specific to the apical, but not the basilar, dendrites of CA1. Clustering of synaptic inputs is thought to allow nonlinear summation of synaptic strength. These findings further elucidate neuroplastic changes in glutamatergic circuits with aging and advance therapeutic development to prevent and treat agerelated cognitive decline.cognitive aging | glutamate | riluzole | neuroplasticity | dendritic spine clustering C ognitive decline often occurs with aging in rodents (1), nonhuman primates (2), and humans (3). Memory loss (4) and executive impairment (5) are of the most functional importance, mediated primarily by the hippocampus and related areas of the medial temporal lobe and the prefrontal cortex (PFC), respectively. The neural circuits vulnerable to aging are composed of glutamatergic pyramidal neurons that furnish corticocortical connections between the association cortices as well as the excitatory hippocampal connections (2, 6). Dendritic spine changes, which appear to be the primary site of structural plasticity in the adult brain (7), occur in the pyramidal neurons of the PFC (5) and in the hippocampus (8, 9) with aging and correlate with behavioral decline. Spines form the postsynaptic component of most excitatory synapses in the cerebral cortex and are capable of rapid formation, expansion, contraction, and elimination (10, 11).Synaptic glutamatergic activity is neuroprotective and critical for long-term potentiation (LTP) and memory formation, whereas extrasynaptic NMDA receptor activity promotes longterm depression and excitotoxicity (12, 13). There is some evidence that astrocytic glutamate transporters decrease with aging (14, 15), and conse...