Neural substrates of habit

Abstract

Active reward pursuit is supported by the balance between the cognitive and habitual control of behavior. The cognitive, goal-directed strategy relies on the prospective evaluation of anticipated consequences, which allows behavior to readily adapt when circumstances change. Repetition of successful actions promotes less cognitively taxing habits, in which behavior is automatically executed without prospective consideration. Disruption in either of these behavioral regulatory systems contributes to the symptoms that underlie many psychiatric disorders. Here, I review recently identified neural substrates, at multiple neural levels, that contribute to habits and outline gaps in knowledge that must be addressed to fully understand the neural mechanisms of behavioral control.

Keywords: HDAC3; behavioral control; epigenetics; goal-directed; habits; plasticity; striatum.

Figure 1.. Striatal cell-types and potential interactions regulating behavioral control.

The dorsomedial (DMS) and dorsolateral striatum (DLS) both contain spiny projection neurons (SPNs), that directly (dSPNs) or indirectly (iSPNs) project to basal ganglia output nuclei, as well as various interneurons such as fast-spiking interneurons (FSIs), tyrosine-hydroxylase expressing interneurons (THINs), and cholinergic interneurons (CINs). These interneurons can modulate the activity of SPNs to differentially affect goal-directed and habitual behavior, however, several of the interactions between the specific cell-types have not been delineated in the context of goal-directed and habit behaviors.

Figure 2.. Striatal output activity is regulated by G-protein coupled receptors and contributes to behavioral control.

In the dorsomedial striatum (DMS), G-protein coupled receptors are known to modulate spiny projection neuron (SPN) activity. (a) Adenosine A2A receptors (A2ARs), exclusively expressed in indirect output pathway spiny projection neurons (iSPNs), contain the activating G-protein (Gs). A2AR activation in the DMS increases the inhibitory activity of the indirect output pathway (iSPN), ultimately inhibiting goal-directed behavior. Conversely, inhibiting A2ARs in the DMS prevents the inhibitory iSPN output activity, thereby enhancing goal-directed behavior. (b) Excitatory input from the orbitofrontal cortex (OFC) increases DMS direct pathway spiny projection neuron (dSPN) output activity and is necessary for goal-directed behavior. (c) OFC pre-synaptic activity in the DMS is negatively regulated by the cannabinoid type 1 (CB1) that is coupled to inhibitory G-proteins (Gi), which causes reduced dSPN activity and suppresses goal-directed behavior, rendering animals habitual.

Figure 3.. Striatal subregion-specific activation of intracellular signaling mechanisms differentially regulates behavioral control.

The extracellular signal-related kinase (ERK) pathway is activated in the dorsal striatum during instrumental learning and may potentially contribute to the transcription necessary for synaptic plasticity. (a,b) The tyrosine receptor kinase B (TrkB), the receptor for brain-derived neurotrophic factor (BDNF), is a potential upstream mechanism of ERK activation in both the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). (a) In the DMS, TrkB activation is necessary for goal-directed behavior, (b) whereas in the DLS TrkB activation contributes to habits. In the DLS, (b) the proton-gated acid-sensing ion channel isoform ASIC1a activates ERK signaling and is necessary for motor learning. It is unknown whether ASIC1a contributes specifically to instrumental habit learning.

Figure 4.. HDAC3 negatively regulates habits in the DMS and DLS.

Histone modifications regulate the access to DNA for the transcriptional machinery and are fundamental in neuronal function and memory. (a) Early in instrumental training, when behavior is goal-directed, the transcriptional repressor histone deacetylase 3 (HDAC3) is engaged near gene promoters, removing acetyl groups from the histone’s N-terminal tails, creating a transcriptionally repressive chromatin state where DNA is less accessible to the transcriptional machinery. (b) With sufficient training, when animals become habitual, HDAC3 is disengaged from gene promoters by allowing the addition of acetyl groups (Ac) to the histone tails, which neutralized the interaction between the DNA and histone tails and leads to a relaxed chromatin state. This allows for the transcription of plasticity-related genes. It is unknown which histone acetyltransferase (HAT) contributes to this process and how these mechanisms are activated.