iNIRKO hippocampal gene expression analysis
Depression is a leading cause of global disability and is increasingly linked to systemic metabolic dysfunctions, including insulin resistance, yet the biological pathways connecting metabolic state to affective symptoms remain unresolved. Insulin is a key regulator of systemic glucose homeostasis and emerging evidence suggests that insulin signalling in the brain supports metabolism, synaptic function and cognition, but its role in mood regulation remains unclear.  Here, we identify a hippocampal metabolic signature associated with glycaemic variation in individuals with depression. Using multimodal neuroimaging, we show that hippocampal concentrations of GABA and lactate correlate with HbA1c and with mood severity, while functional connectivity between the hippocampus and the default mode network tracks affective symptoms independently of adiposity. To causally probe these relationships, we generated a mouse model of hippocampus-specific insulin receptor depletion. Unexpectedly, reducing insulin signalling at the blood brain barrier enhanced neuronal metabolism and attenuated anxiety-like behaviour. Notably, hippocampal lactate and GABA levels similarly tracked anxiety-related behaviour in mice, mirroring their association with symptom severity in humans.  Together, these findings identify a conserved neurometabolic signature linking hippocampal insulin signalling to affective state, and reveal that brain insulin resistance exerts context- and cell-type-specific effects on behaviour. This work establishes a mechanistic basis for brain insulin resistance in depression and highlights the hippocampus as a critical hub for metabolic modulation of mood.
Depression is a leading cause of global disability and is increasingly linked to systemic metabolic dysfunctions, including insulin resistance, yet the biological pathways connecting metabolic state to affective symptoms remain unresolved. Insulin is a key regulator of systemic glucose homeostasis and emerging evidence suggests that insulin signalling in the brain supports metabolism, synaptic function and cognition, but its role in mood regulation remains unclear.  Here, we identify a hippocampal metabolic signature associated with glycaemic variation in individuals with depression. Using multimodal neuroimaging, we show that hippocampal concentrations of GABA and lactate correlate with HbA1c and with mood severity, while functional connectivity between the hippocampus and the default mode network tracks affective symptoms independently of adiposity. To causally probe these relationships, we generated a mouse model of hippocampus-specific insulin receptor depletion. Unexpectedly, reducing insulin signalling at the blood brain barrier enhanced neuronal metabolism and attenuated anxiety-like behaviour. Notably, hippocampal lactate and GABA levels similarly tracked anxiety-related behaviour in mice, mirroring their association with symptom severity in humans.  Together, these findings identify a conserved neurometabolic signature linking hippocampal insulin signalling to affective state, and reveal that brain insulin resistance exerts context- and cell-type-specific effects on behaviour. This work establishes a mechanistic basis for brain insulin resistance in depression and highlights the hippocampus as a critical hub for metabolic modulation of mood.
University of Oxford