Disruption of Nrxn1α within excitatory forebrain circuits drives value-based dysfunction

Abstract

Goal-directed behaviors, complex action sequences that maximize reward, are essential for normal function and are significantly impaired across neuropsychiatric disorders. Despite extensive associations between genetic mutations and these brain disorders, the mechanisms by which candidate genes contribute to goal-directed dysfunction remains unclear, owing to challenges in (1) describing aspects of reward processing that drive goal-directed dysfunction, (2) localizing these deficits to specific brain circuits and (3) relating changes in physiology to behavioral alterations. Here we examined mice with mutations in Neurexin1α, a presynaptically-localized adhesion molecule with widespread neuropsychiatric disease association, in value-based decision-making paradigms. We found that Neurexin1α knockout animals exhibited blunted choice bias towards outcomes associated with greater benefits. Mutant mice were similarly impaired in avoiding costlier, benefit-neutral actions. Analysis of trial-by-trial choice data via reinforcement learning models suggested these behavioral patterns were driven largely by deficits in the updating and representation of choice values. Employing conditional gene ablation and region-specific Cre-recombinase strains, we revealed that Neurexin1α disruption within forebrain excitatory projection neurons, but not thalamic populations, recapitulated most aspects of the whole-brain knockout phenotype. Finally, utilizing in vivo recordings of direct pathway spiny neuron population calcium activity, we demonstrated that selective knockout of Neurexin1α within forebrain excitatory neurons disrupts reward-associated neural signals within striatum, a major site of feedbackbased learning. By relating deficits in value-based decision-making to region-specific Nrxn1α disruption and changes in reward-associated neural activity, we reveal potential neural substrates for the pathophysiology of neuropsychiatric disease-associated cognitive dysfunction. Genotype: p=0.049 Reward: p<.0001 Interaction: p=0.025 Figure 8 Nex-Control (n=7) Nex-Nrxn1α cKO (n=6) Nex-Control (n=7) Nex-Nrxn1α cKO (n=6) Large Reward (t-1) Small Reward (t-1) * ΔQ*temp -1 (t)

Training-Induced Circuit-Specific Excitatory Synaptogenesis is Required for Effort Control

“…Our findings show that loss of α2δ-1-signalling disrupts this adaptive step. We used the PR test to measure effort exertion, because it avoids the confound of having to select between different options, such as choosing between two actions with different probability of reward or two different locations with different rewards 20,38,40,68,93,94 . In fact, PR test is a standard test to measure effort exertion both in rodents and humans 37,[84][85][86] .…”

“…For example, learning the action-outcome relationship requires the dorsomedial striatum (DMS) 29, 32 , which is a hub for many cortical inputs 33, 34 . Particularly, the inputs coming from the prefrontal cortex (PFC) to the DMS play critical roles in instrumental training, such as learning the action- outcome contingency 31, 35, 36 , evaluation of an outcome’s value 30, 37, 38 , and deciding between different actions or outcomes 39, 40 . However, the cellular and molecular mechanisms underlying the remodeling of these cortico-striatal circuits during learning and how their functions control goal-directed actions are unknown.…”

Neurexin1α differentially regulates synaptic efficacy within striatal circuits

“…It is an interesting future question as to whether this thalamic disinhibition can explain both simple motor phenotypes (e.g. hyperactivity, aggression) (Etherton et al, 2009;Grayton et al, 2013) and more complex reward processing deficits observed in mice with Nrxn1α mutations (Alabi et al, 2019). It is worth noting a recent study of the Tsc1 deletion ASD mouse model, which exhibited increased corticostriatal connectivity selectively onto dSPNs, with synaptic strength unperturbed at thalamostriatal synapses (Benthall et al, 2018).…”