Adaptively Timed Learning

This chapter explains how humans and other animals learn to adaptively time their behaviors to match external environmental constraints. It hereby explains how nerve cells learn to bridge big time intervals of hundreds of milliseconds or even several seconds, and thereby associate events that are separated in time. This is accomplished by a spectrum of cells that each respond in overlapping time intervals and whose population response can bridge intervals much larger than any individual cell can. Such spectral timing occurs in circuits that include the lateral entorhinal cortex and hippocampal cortex. Trace conditioning, in which CS and US are separated in time, requires the hippocampus, whereas delay conditioning, in which they overlap, does not. The Weber law observed in trace conditioning naturally emerges from spectral timing dynamics, as later confirmed by data about hippocampal time cells. Hippocampal adaptive timing enables a cognitive-emotional resonance to be sustained long enough to become conscious of its feeling and its causal event, and to support BDNF-modulated memory consolidation. Spectral timing supports balanced exploratory and consummatory behaviors whereby restless exploration for immediate gratification is replaced by adaptively timed consummation. During expected disconfirmations of reward, orienting responses are inhibited until an adaptively timed response is released. Hippocampally-mediated incentive motivation supports timed responding via the cerebellum. mGluR regulates adaptive timing in hippocampus, cerebellum, and basal ganglia. Breakdowns of mGluR and dopamine modulation cause symptoms of autism and Fragile X syndrome. Inter-personal circular reactions enable social cognitive capabilities, including joint attention and imitation learning, to develop.

Cholinergic neurons constitutively engage the ISR for dopamine modulation and skill learning in mice

The integrated stress response (ISR) maintains proteostasis by modulating protein synthesis and is important in synaptic plasticity, learning, and memory. We developed a reporter, SPOTlight, for brainwide imaging of ISR state with cellular resolution. Unexpectedly, we found a class of neurons in mouse brain, striatal cholinergic interneurons (CINs), in which the ISR was activated at steady state. Genetic and pharmacological manipulations revealed that ISR signaling was necessary in CINs for normal type 2 dopamine receptor (D2R) modulation. Inhibiting the ISR inverted the sign of D2R modulation of CIN firing and evoked dopamine release and altered skill learning. Thus, a noncanonical, steady-state mode of ISR activation is found in CINs, revealing a neuromodulatory role for the ISR in learning.

The Potential Role of Dopamine in Mediating Motor Function and Interpersonal Synchrony

Motor functions in general and motor planning in particular are crucial for our ability to synchronize our movements with those of others. To date, these co-occurring functions have been studied separately, and as yet it is unclear whether they share a common biological mechanism. Here, we synthesize disparate recent findings on motor functioning and interpersonal synchrony and propose that these two functions share a common neurobiological mechanism and adhere to the same principles of predictive coding. Critically, we describe the pivotal role of the dopaminergic system in modulating these two distinct functions. We present attention deficit hyperactivity disorder (ADHD) as an example of a disorder that involves the dopaminergic system and describe deficits in motor and interpersonal synchrony. Finally, we suggest possible directions for future studies emphasizing the role of dopamine modulation as a link between social and motor functioning.