Neurobiology of the lateral septum: regulation of social behavior

The many facets of the oxytocin (OXT) system of the brain and periphery elicited nearly 25,000 publications since 1930 (see FIGURE 1 , as listed in PubMed), which revealed central roles for OXT and its receptor (OXTR) in reproduction, and social and emotional behaviors in animal and human studies focusing on mental and physical health and disease. In this review, we discuss the mechanisms of OXT expression and release, expression and binding of the OXTR in brain and periphery, OXTR-coupled signaling cascades, and their involvement in behavioral outcomes to assemble a comprehensive picture of the central and peripheral OXT system. Traditionally known for its role in milk let-down and uterine contraction during labor, OXT also has implications in physiological, and also behavioral, aspects of reproduction, such as sexual and maternal behaviors and pair bonding, but also anxiety, trust, sociability, food intake, or even drug abuse. The many facets of OXT are, on a molecular basis, brought about by a single receptor. The OXTR, a 7-transmembrane G protein-coupled receptor capable of binding to either Gαi or Gαq proteins, activates a set of signaling cascades, such as the MAPK, PKC, PLC, or CaMK pathways, which converge on transcription factors like CREB or MEF-2. The cellular response to OXT includes regulation of neurite outgrowth, cellular viability, and increased survival. OXTergic projections in the brain represent anxiety and stress-regulating circuits connecting the paraventricular nucleus of the hypothalamus, amygdala, bed nucleus of the stria terminalis, or the medial prefrontal cortex. Which OXT-induced patterns finally alter the behavior of an animal or a human being is still poorly understood, and studying those OXTR-coupled signaling cascades is one initial step toward a better understanding of the molecular background of those behavioral effects.

The medial temporal lobe, including the hippocampus, has been implicated in social memory. However, it remains unknown which parts of these brain regions and their circuits hold social memory. Here, we show that ventral hippocampal CA1 (vCA1) neurons of a mouse and their projections to nucleus accumbens (NAc) shell play a necessary and sufficient role in social memory. Both the proportion of activated vCA1 cells and the strength and stability of the responding cells are greater in response to a familiar mouse than to a previously unencountered mouse. Optogenetic reactivation of vCA1 neurons that respond to the familiar mouse enabled memory retrieval and the association of these neurons with unconditioned stimuli. Thus, vCA1 neurons and their NAc shell projections are a component of the storage site of social memory.

Infantile autism is a behaviorally defined disorder associated with characteristic cognitive, language and behavioral features. Several postmortem studies have highlighted areas of anatomic abnormality in the autistic brain. Consistent findings have been observed in the limbic system, cerebellum and related inferior olive. In the limbic system, the hippocampus, amygdala and entorhinal cortex have shown small cell size and increased cell packing density at all ages, suggesting a pattern consistent with development curtailment. Findings in the cerebellum have included significantly reduced numbers of Purkinje cells, primarily in the posterior inferior regions of the hemispheres. A different pattern of change has been noted in the vertical limb of the diagonal band of broca, cerebellar nuclei and inferior olive with plentiful and abnormally enlarged neurons in the brains of young autistic subjects, and in adult autistic brains, small, pale neurons that are reduced in number. These findings combined with reported age-related changes in brain weight and volume, have raised the possibility that the neuropathology of autism may represent an on-going process.