Abstract
The lateral septum has strong efferent projections to hypothalamic and midbrain regions, and has been associated with modulation of social behavior, anxiety, fear conditioning, memory-related behaviors, and the mesolimbic reward pathways. Understanding natural variation of lateral septal anatomy and function, as well as its genetic modulation, may provide important insights into individual differences in these evolutionarily important functions. Here we address these issues by using efficient and unbiased stereological probes to estimate the volume of the lateral septum in the BXD line of recombinant inbred mice. Lateral septum volume is a highly variable trait, with a 2.5-fold difference among animals. We find that this trait covaries with a number of behavioral and physiological phenotypes, many of which have already been associated with behaviors modulated by the lateral septum, such as spatial learning, anxiety, and reward-seeking. Heritability of lateral septal volume is moderate (h 2 = 0.52), and much of the heritable variation is caused by a locus on the distal portion of chromosome (Chr) 1. Composite interval analysis identified a secondary interval on Chr 2 that works additively with the Chr 1 locus to increase lateral septum volume. Using bioinformatic resources, we identified plausible candidate genes in both intervals that may influence the volume of this key nucleus, as well as associated behaviors.
Highlights
The septum, a key component of the limbic system, is involved in the control of a wide variety of functions, including emotions, learning and memory, fear, reward-seeking behavior, and modulation of autonomic functions
Lateral Septal Volume is Highly Variable All estimates of lateral septum (LS) volume are corrected on a case-by-case basis for shrinkage and should be considered close to the original size of these regions in well-fixed tissue
Lateral Septal Volume is Highly Heritable In order to assess heritability, we computed an ANOVA with strain as the independent measure and LS volume as the dependent measure
Summary
The septum, a key component of the limbic system, is involved in the control of a wide variety of functions, including emotions, learning and memory, fear, reward-seeking behavior, and modulation of autonomic functions. The septum is divided into the lateral, medial, and posterior nuclei, with the former two nuclei comprising the largest portion of the septum. These nuclei have distinct patterns of connectivity and physiology and are each associated with modulation of different functions. The lateral septum receives substantial glutamatergic afferent projections from the hippocampus and amygdala, and has been associated with a number of memory-related behaviors [10,11,12]
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