Structure-function subsystem models of female and male forebrain networks integrating cognition, affect, behavior, and bodily functions.

The forebrain is the first of three primary vertebrate brain subdivisions. Macrolevel network analysis in a mammal (rat) revealed that the 466 gray matter regions composing the right and left sides of the forebrain are interconnected by 35,738 axonal connections forming a large set of overlapping, hierarchically arranged subsystems. This hierarchy is bilaterally symmetrical and sexually dimorphic, and it was used to create a structure-function conceptual model of intraforebrain network organization. Two mirror image top-level subsystems are presumably the most fundamental ontogenetically and phylogenetically. They essentially form the right and left forebrain halves and are relatively weakly interconnected. Each top-level subsystem in turn has two second-level subsystems. A ventromedial subsystem includes the medial forebrain bundle, functionally coordinating instinctive survival behaviors with appropriate physiological responses and affect. This subsystem has 26/24 (female/male) lowest-level subsystems, all using a combination of glutamate and GABA as neurotransmitters. In contrast, a dorsolateral subsystem includes the lateral forebrain bundle, functionally mediating voluntary behavior and cognition. This subsystem has 20 lowest-level subsystems, and all but 4 use glutamate exclusively for their macroconnections; no forebrain subsystems are exclusively GABAergic. Bottom-up subsystem analysis is a powerful engine for generating testable hypotheses about mechanistic explanations of brain function, behavior, and mind based on underlying circuit organization. Targeted computational (virtual) lesioning of specific regions of interest associated with Alzheimer's disease, clinical depression, and other disorders may begin to clarify how the effects spread through the entire forebrain network model.