Abstract
Archaerhodopsin (ArchT)-mediated photoinhibition of axon terminals is commonly used to test the involvement of specific long-range neural projections in behavior. Although sustained activation of this opsin in axon terminals has the unintended consequence of enhancing spontaneous vesicle release, it is unclear whether this desynchronized signaling is consequential for ArchT’s behavioral effects. Here, we compare axon terminal and cell body photoinhibition of nucleus accumbens (NAc) afferents to test the utility of these approaches for uncovering pathway-specific contributions of neural circuits to behavior. First, in brain slice recordings we confirmed that ArchT photoinhibition of glutamatergic axons reduces evoked synaptic currents and increases spontaneous transmitter release. A further consequence was increased interneuron activity, which served to broadly suppress glutamate input via presynaptic GABAB receptors. In vivo, axon terminal photoinhibition increased feeding and reward-seeking behavior irrespective of the afferent pathway targeted. These behavioral effects are comparable to those obtained with broad inhibition of NAc neurons. In contrast, cell body inhibition of excitatory NAc afferents revealed a pathway-specific contribution of thalamic input to feeding behavior and amygdala input to reward-seeking under extinction conditions. These findings underscore the off-target behavioral consequences of ArchT-mediated axon terminal inhibition while highlighting cell body inhibition as a valuable alternative for pathway-specific optogenetic silencing.
Highlights
The nucleus accumbens (NAc) is a forebrain structure that regulates the vigor of rewardseeking
Photoinhibition of paraventricular thalamic (PVT) and basolateral amygdala (BLA) axons in the NAc increased the frequency of active lever pressing (Figures 1B,C), whereas intracranial light delivery in GFP-only control mice did not affect reward-seeking behavior
These behavioral effects are comparable to those obtained with direct NAc neuron photoinhibition (O’Connor et al, 2015) and NAc lesions (Bowman and Brown, 1998), which suggests that any inhibitory influence on NAc physiology may disinhibit reward-seeking
Summary
The nucleus accumbens (NAc) is a forebrain structure that regulates the vigor of rewardseeking. Its excitatory inputs likely encode motivational states and the presence of rewardassociated cues (Mannella et al, 2013). Paraventricular thalamic (PVT) input regulates food-seeking behavior under conditions of hunger and threat (Labouèbe et al, 2016; Choi and McNally, 2017; Do-Monte et al, 2017; Cheng et al, 2018; Choi et al, 2019), while basolateral amygdala (BLA) input encodes the motivational value of rewardassociated cues (Ambroggi et al, 2008; Stuber et al, 2011; Esber and Holland, 2014). Few studies have directly compared the behavioral consequences of pathway-specific manipulations, so it remains unclear how each input distinctly contributes to effective rewardseeking. Pathwayspecific inactivation of these inputs is critical to gaining insight into how this circuitry contributes to healthy and unhealthy behavior alike
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