Progressive Circuit Changes during Learning and Disease

Abstract

A critical step toward understanding cognition, learning, and brain dysfunction will be identification of the underlying cellular computations that occur in and across discrete brain areas, as well as how they are progressively altered by experience or disease. These computations will be revealed by targeted analyses of the neurons that perform these calculations, defined not only by their firing properties but also by their molecular identity and how they are wired within the local and broad-scale network of the brain. New studies that take advantage of sophisticated genetic tools for cell-type-specific identification and control are revealing how learning and neurological disorders initiate and successively change the properties of defined neural circuits. Understanding the temporal sequence of adaptive or pathological synaptic changes across multiple synapses within a network will shed light into how small-scale neural circuits contribute to higher cognitive functions during learning and disease.

Figure 1.. Rewiring of neocortical excitatory connections during learning.

A) Schematic of thalamic inputs (blue) to L2 (top), L4 (center), and L5 (bottom) excitatory neurons. B) Higher-order thalamic inputs to L5 Pyr neurons change rapidly (Audette et al, 2019; Biane et al, 2019). It is unknown how thalamic drive or feedforward inhibition from PV neurons changes during the early stages of sensory or motor learning (grey). C) Higher-order thalamic inputs to L2 Pyr neurons change later, and synaptic strength between L2 Pyr neurons is also increased (Audette et al, 2019). The changes in PV inhibition during early sensory learning have not been well-characterized.

Figure 2.. Inhibitory synaptic motifs in the neocortex.

A) Synaptic connectivity between VIP, SST, and PV neurons. Left, Serial inhibition from VIP to SST to PV, so that VIP and PV activity are positively coupled and the major effect is Pyr inhibition. Right, Parallel inhibition of Pyr from both SST and PV neurons suggests that VIP activity may reduce SST without altering PV inhibition. B) Potential scenarios for state-dependent disinhibition during learning. Left, the primary effect of increased VIP firing during learning is suppression of SST activity and enhanced PV inhibition onto Pyr neurons. Right, the primary effect of increased VIP firing during learning is reduced SST inhibition onto Pyr neurons. C) Anatomical and electrophysiological data indicates sensory experience decreases PV inhibition onto Pyr neurons.

Figure 3.. Progressive circuit changes in the hippocampal CA1 circuit during AD.

The schematic demonstrates gradual changes in the different synaptic inputs onto a CA1 pyramidal neuron (in black) across stages of AD pathology. Entorhinal cortex (EC, blue) and CA3 (black) represent two major excitatory inputs, while PV and SST represent two major inhibitory inputs to the CA1 Pyr. A) In the healthy condition, different excitatory inputs are balanced by a combination of inhibition ensuring normal activity levels of the CA1 pyr. B) During early stages of AD, CA1 Pyr may become hyperactive due to a combination of decreased inhibition as well as an increase in excitation mediated by low levels of Aβ hypothetically through blocking of GABA signaling, strengthening of LTP, axonal sprouting, and/or decreased glutamate reuptake may result in hyperactivity. EC inputs may be more susceptible to early Aβ-pathology even in earlier stages. C) During later stages, high Aβ levels may affect synapses globally - by blocking NMDAR signaling, impairing LTP, strengthening LTD, excessive synaptic pruning and/or axonal dystrophy - resulting in hypoactivity.