Seminars

Different brain cell types exhibit distinct metabolic signatures that link energy economy to cellular function. Astrocytes and neurons, for instance, diverge dramatically in their reliance on glycolysis versus oxidative phosphorylation, underscoring that metabolic fuel efficiency is not uniform across cell types. A key factor shaping this divergence is the structural organization of the mitochondrial respiratory chain into supercomplexes. Specifically, complexes I (CI) and III (CIII) form a CI–CIII supercomplex, but the degree of this assembly varies by cell type. In neurons, CI is predominantly integrated into supercomplexes, resulting in highly efficient mitochondrial respiration and minimal reactive oxygen species (ROS) generation. Conversely, in astrocytes, a larger fraction of CI remains unassembled, freely existing apart from CIII, leading to reduced respiratory efficiency and elevated mitochondrial ROS production. Despite this apparent inefficiency, astrocytes boast a highly adaptable metabolism capable of responding to diverse stressors. Their looser CI–CIII organization allows for flexible ROS signaling, which activates antioxidant programs via transcription factors like Nrf2. This modular architecture enables astrocytes not only to balance energy production but also to support neuronal health and influence complex organismal behaviors.

Biological neural networks can represent information in the collective action potential discharge of neurons, and store that information amongst the synaptic connections between the neurons that both comprise the network and govern its function. The strength and organization of synaptic connections adjust during learning, but many cognitive neural systems are multifunctional, making it unclear how continuous activity alternates between the transient and discrete cognitive functions like encoding current information and recollecting past information, without changing the connections amongst the neurons. This lecture will first summarize our investigations of the molecular and biochemical mechanisms that change synaptic function to persistently store spatial memory in the rodent hippocampus. I will then report on how entorhinal cortex-hippocampus circuit function changes during cognitive training that creates memory, as well as learning to learn in mice. I will then describe how the hippocampus system operates like a competitive winner-take-all network, that, based on the dominance of its current inputs, self organizes into either the encoding or recollection information processing modes. We find no evidence that distinct cells are dedicated to those two distinct functions, rather activation of the hippocampus information processing mode is controlled by a subset of dentate spike events within the network of learning-modified, entorhinal-hippocampus excitatory and inhibitory synapses.

A long-term treatment with antidepressants reduces the risk to develop AD and different second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are currently studied for their neuroprotective properties in AD. An impairment of neurotrophic factors signaling seems to be a common pathophysiological event in depression and AD. In particular a deficit of transforming growth factor-β1 (TGF-β1) and increased oxidative stress have been found both in depression and AD. In the present work the SSRI fluoxetine and the new multimodal antidepressant vortioxetine were tested for their ability to prevent memory deficits and depressive-like phenotype in a non-transgenic mouse model of AD (i.c.v. Aβ1-42 injection) by rescue of TGF-β1 signaling. The same drugs were also tested for their ability to modulate the expression of pro-oxidant genes as well as of genes related to the antioxidant machinery.