An energy costly architecture of neuromodulators for human brain evolution and cognition

Abstract

Humans spend more energy on the brain than any other species. However, the high energy demand cannot be fully explained by brain size scaling alone. We hypothesized that energy-demanding signaling strategies may have contributed to human cognitive development. We measured the energy distribution along signaling pathways using multimodal brain imaging and found that evolutionarily novel connections have up to 67% higher energetic costs of signaling than sensory-motor pathways. Additionally, histology, transcriptomic data, and molecular imaging independently reveal an upregulation of signaling at G-protein coupled receptors in energy-demanding regions. We found that neuromodulators are predominantly involved in complex cognition such as reading or memory processing. Our study suggests that the upregulation of neuromodulator activity, alongside increased brain size, is a crucial aspect of human brain evolution.

A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity

“…2n). This enzymatic specialization aligns with the hypothesis that an evolutionary gradient exists with an increased metabolic demand 12 . Our data show that this demand is met by a specialized mitochondrial phenotype with high OxPhos capacity per mitochondrion.…”

“…Functional neuroimaging techniques capture dynamic electrical, metabolic and hemodynamic brain energy states 12–15 but offer only indirect measures of the underlying subcellular bioenergetic processes. All basal and activity-dependent brain processes depend on cellular energy transformation, or bioenergetics, involving ATP synthesis by oxidative phosphorylation (OxPhos) within trillions of respiring mitochondria 16 .…”

A neurometabolic signature in the frontal cortex explains individual differences in effort-based decision-making

“…Therefore, of the number of metabolites collected from each participant, the most discriminating variables contributing to motivated behavior in our mental effort task include features that were related to energetic pathways. Energy is of peculiar importance as, notably, the dmPFC/dACC selected in our study, is one of the regions with the highest energy consumption of the brain (Castrillon et al, 2023; Raichle & Mintun, 2006). At a regional level, regions like the dmPFC/dACC that expanded most during human evolution show an excessive energy demand compared to the rest of the brain.…”

Sex differences in intrinsic functional cortical organization reflect differences in network topology rather than cortical morphometry

“…The balance between integration and segregation is complex, dynamic, and necessary to maintain the brain’s metastability [53] by reaching a point of equilibrium between global organization and local specialization [43]. The brain is a highly interconnected and metabolically expensive organ, and its organization is required to dynamically balance topological efficiency and energy utilization in response to transient cognitive and physiological demands [54]. Our findings of sex differences in network topology may therefore pertain to intricate sex differences not only in brain states at rest, which may underpin cognitive differences, but also in energy expenditure, which would reflect physiological differences.…”