Desire or Dread from Nucleus Accumbens Inhibitions: Reversed by Same-Site Optogenetic Excitations

Abstract

Microinjections of a glutamate AMPA antagonist (DNQX) in medial shell of nucleus accumbens (NAc) can cause either intense appetitive motivation (i.e., 'desire') or intense defensive motivation (i.e., 'dread'), depending on site along a flexible rostrocaudal gradient and on environmental ambience. DNQX, by blocking excitatory AMPA glutamate inputs, is hypothesized to produce relative inhibitions of NAc neurons. However, given potential alternative explanations, it is not known whether neuronal inhibition is in fact necessary for NAc DNQX microinjections to generate motivations. Here we provide a direct test of whether local neuronal inhibition in NAc is necessary for DNQX microinjections to produce either desire or dread. We used optogenetic channelrhodopsin (ChR2) excitations at the same local sites in NAc as DNQX microinjections to oppose relative neuronal inhibitions induced by DNQX in female and male rats. We found that same-site ChR2 excitation effectively reversed the ability of NAc DNQX microinjections to generate appetitive motivation, and similarly reversed ability of DNQX microinjections to generate defensive motivation. Same-site NAc optogenetic excitations also attenuated recruitment of Fos expression in other limbic structures throughout the brain, which was otherwise elevated by NAc DNQX microinjections that generated motivation. However, to successfully reverse motivation generation, an optic fiber tip for ChR2 illumination needed to be located within Ͻ1 mm of the corresponding DNQX microinjector tip; that is, both truly at the same NAc site. Thus, we confirm that localized NAc neuronal inhibition is required for AMPA-blocking microinjections in medial shell to induce either positively-valenced 'desire' or negatively-valenced 'dread'.

Optogenetics and Controlling the Human Mind

“…As part of the mesolimbic reward pathway between the prefrontal cortex and the emotional limbic system, the NAcc facilitates subjective experiences of pleasure when introduced to favorable stimuli. Studies have shown that stimulation of the NAcc can effectively increase feeding behavior of rats (Baumgartner et al, 2020). Additionally, deep brain stimulation technologies that increase neural firing in the NAcc are approved for the treatment of depression in humans by relieving symptoms of anhedonia (lack of pleasure) (Delaloye & Holtzheimer, 2014).…”

“…Because optogenetics allows instant and selective stimulation of any brain area, optogenetic neurons in the NTS and NAcc could be stimulated to decrease or increase desired behaviors. A study by Baumgartner et al (2020) tested optogenetic stimulation in mice. The study used CRISPR to implant opsins in different areas of the NAcc and found that, depending on the location of stimulation, both desire and dread could be reliably induced by optogenetic stimulation (Baumgartner et al, 2020).…”

“…A study by Baumgartner et al (2020) tested optogenetic stimulation in mice. The study used CRISPR to implant opsins in different areas of the NAcc and found that, depending on the location of stimulation, both desire and dread could be reliably induced by optogenetic stimulation (Baumgartner et al, 2020). It appears that operant conditioning is already possible with optogenetics, but how could this technology be used similarly in humans?…”

Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation

“…The NAc is a critical hub involved in motivation for various rewards, such as food and drugs of abuse, as well as fear and aversion [ 4 , 5 ]. The NAc is primarily comprised of medium spiny neurons (MSNs) of two distinct subpopulations: D1-MSNs and D2-MSNs [ 6 , 7 ].…”

Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation

“…In the nucleus accumbens (NAc) mitochondrial fission or molecules related to mitochondrial dynamics and function are altered by cocaine 1,2 . The NAc is a critical hub involved in motivation for various rewards, such as food, sex, and drugs of abuse, as well as fear and aversion 4,5 .…”