Metabolic tuning of inhibition regulates hippocampal neurogenesis in the adult brain

Abstract

Hippocampus-engaged behaviors stimulate neurogenesis in the adult dentate gyrus by largely unknown means. To explore the underlying mechanisms, we used tetrode recording to analyze neuronal activity in the dentate gyrus of freely moving adult mice during hippocampus-engaged contextual exploration. We found that exploration induced an overall sustained increase in inhibitory neuron activity that was concomitant with decreased excitatory neuron activity. A mathematical model based on energy homeostasis in the dentate gyrus showed that enhanced inhibition and decreased excitation resulted in a similar increase in neurogenesis to that observed experimentally. To mechanistically investigate this sustained inhibitory regulation, we performed metabolomic and lipidomic profiling of the hippocampus during exploration. We found sustainably increased signaling of sphingosine-1-phosphate, a bioactive metabolite, during exploration. Furthermore, we found that sphingosine-1-phosphate signaling through its receptor 2 increased interneuron activity and thus mediated exploration-induced neurogenesis. Taken together, our findings point to a behavior-metabolism circuit pathway through which experience regulates adult hippocampal neurogenesis.

Amygdala Allostasis and Early Life Adversity: Considering Excitotoxicity and Inescapability in the Sequelae of Stress

“…In a way, the amygdala may reach a breaking point of over-excitation that leads to smaller structural volumes, while higher functional reactivity and excitatory tone are still present. This fits with the smaller volumes typically noted in adult samples exposed to stress, echoing rodent hippocampal models predicting that high ratios of inhibitory neurons are metabolically more costly if unable to reduce high firing rates of excitatory neurons (Wang et al, 2020). As such, we predict that individuals with the largest volumes in early childhood and smallest volumes after the first decade of life will manifest highest levels of symptomatology, likely presenting with one or more full-blown clinical diagnoses.…”

“…In regard to allostatic load of the amygdala and nearby structures, recent preclinical work shows that neurogenesis in hippocampus is highly constrained by the metabolic costs of deviating from an optimal ratio of excitatory to inhibitory neuronal firing (Wang et al, 2020). Considering metabolic costs of excitation-inhibition ratios in the amygdala (Figures 2, 3), the basolateral portions are primarily excitatory with a large concentration of glutamate (Glu) releasing neurons, but under resting conditions an extensive network of inhibitory, γ-aminobutyric acid (GABA) releasing neurons anchored in the paralaminar zone largely silences the basolateral complex (Quirk and Gehlert, 2003).…”

Shifted Dynamics of Glucose Metabolism in the Hippocampus During Aging

“…Endogenous neurogenesis, neural circuit plasticity, and cognitive function in the hippocampus all decline during aging (Mattson and Arumugam, 2018 ). Recent studies, including the work from our group, have shown that the hippocampus, a key brain area for episodic memory, exhibits dramatic changes in concentration of metabolites related to energy consumption altered by a behavior task (McNay et al, 2000 ; Wang et al, 2020 ). While previous studies have shown the declining functionality of the aging hippocampus, the causes underlying this decay remain largely unknown.…”

“…We arranged a cohort of 12 male mice that were 6-weeks-old and another cohort of 12 male mice that were 78-weeks-old. Six of the mice of each age were housed in a cage with 4–6 novel objects (wood blocks and plastic balls, 100–200 cm 3 ), defined as an enriched environment group (EE), to increase context exploration as we have previously described (Shen et al, 2019 ; Wang et al, 2020 ). All mice were tested in a plastic cage (24.5 × 47 cm) with wood bedding.…”

Microglia modulate stable wakefulness via the thalamic reticular nucleus in mice

“…Sphingosine-1-phosphate (S1P) is a main catabolite of ceramide 82 . A recent work from our group revealed that sphingosine-1-phosphate receptor 2 (S1PR2) is specifically located in interneuron, with remarkable expression in interneuron enriched TRN region 83 . Manipulations of S1P signaling via S1PR2 tune inhibition level in the neural network 83 .…”