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

Abstract

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.

Subsystem macroarchitecture of the intrinsic midbrain neural network and its tectal and tegmental subnetworks

“…as described in detail elsewhere (ref. 4; also see SI Appendix, Materials and Methods). A comparison of collations by two experts for the same connection matrix (intracerebral cortical network) is provided in ref.…”

“…A validity metric was applied to the pathway-tracing method associated with each connection report (4). The metric uses an ordinal seven-point scale (1 to 7/lowest to highest validity).…”

“…It is well known that changing a brain network's anatomical coverage by adding (or subtracting) subconnectomes commonly alters network features of the component subconnectomes (4,15,19). This phenomenon is obvious when the TC2 and TG2 subconnectomes (Fig.…”

“…Together, these four differentiations or morphogenetic units of the neural tube go on to generate the entire adult central nervous system (2,3). As a major part of a systematic research program to analyze the organizing principles of mammalian nervous system macroconnectivity, we recently completed a study of forebrain intrinsic circuitry (4), and here we present a similar study of MB intrinsic circuitry.…”

Discrete ripples reflect a spectrum of synchronous spiking activity in human association cortex

“…However, our data cannot address whether the relation between ripples and underlying bursts of synchronized spiking is unique to just the temporal lobe or just to memory. Ripples have been most studied in the MTL in both animals and humans, but appear to jointly occur in brain regions that either process or receive the same information (Khodagholy et al, 2017; Lisman & Jensen, 2013; Swanson et al, 2020; Vaz et al, 2019). It is possible that this relation between ripples and spiking activity is unique to brain regions that communicate directly with the MTL or that are directly involved in memory.…”