A Circuit-Based Information Approach to Substance Abuse Research
Authors: David M. Lovinger, Christina M. Gremel
Journal: Trends in Neurosciences (2020)

Behavioral models of compulsive drug use and progress in techniques for cell and circuit measurement and manipulation are advancing substance abuse research.A circuit information-based approach to substance use disorder (SUD)-related research can take full advantage of these developments.This approach moves beyond the assignment of behavior to a particular brain region towards understanding how an area can contribute to the computations performed.We discuss examples from research on the corticothalamic–basal ganglia circuit that highlight the usefulness of circuit information-based research on SUDs.Consideration should also be given to divergent actions of different drugs of abuse in animal model-based research on circuit roles in SUDs. Recent animal research on substance-use disorders (SUDs) has emphasized learning models and the identification of 'addiction-prone' animals. Meanwhile, basic neuroscientific research has elucidated molecular, cellular, and circuit functions with increasing sophistication. However, SUD-related research is hampered by continued arguments over which animal models are more 'addiction like', as well as the facile assignment of behaviors to a given brain region and vice versa. We argue that SUD-related research would benefit from a 'bottom-up' approach including: (i) the characterization of different brain circuits to understand their normal function as well as how they respond to drugs and contribute to SUDs; and (ii) a focus on the use patterns and neurobiological effects of different substances to understand the range of critical SUD-related in vivo phenotypes. Recent animal research on substance-use disorders (SUDs) has emphasized learning models and the identification of 'addiction-prone' animals. Meanwhile, basic neuroscientific research has elucidated molecular, cellular, and circuit functions with increasing sophistication. However, SUD-related research is hampered by continued arguments over which animal models are more 'addiction like', as well as the facile assignment of behaviors to a given brain region and vice versa. We argue that SUD-related research would benefit from a 'bottom-up' approach including: (i) the characterization of different brain circuits to understand their normal function as well as how they respond to drugs and contribute to SUDs; and (ii) a focus on the use patterns and neurobiological effects of different substances to understand the range of critical SUD-related in vivo phenotypes. SUDs (see Glossary) constitute major public health problems, including the effects of excessive intoxication and chronic substance abuse (https://www.niaaa.nih.gov/alcohols-effects-health; https://www.drugabuse.gov/publications/finder/t/160/drugfacts). There are few effective treatments for SUDs and thus further research is needed. Important recent advances have been made in SUD research on human volunteers, including brain imaging, sophisticated behavioral testing, monitoring of drug use and associated behavior, and new pharmaceutical and non-pharmaceutical treatments (e.g., transcranial magnetic stimulation) (https://www.niaaa.nih.gov/alcohol-health/support-treatment; https://www.drugabuse.gov/related-topics/treatmentREF). In SUD-related research using animal models, new behavioral paradigms examine the motivations for drug seeking and taking, as well as decision making affected by and related to abused substances. Models of 'compulsive' drug seeking and taking were developed to study individual animals most vulnerable to disordered use [1.Deroche-Gamonet V. et al.Evidence for addiction-like behavior in the rat.Science. 2004; 305: 1014-1017Crossref PubMed Scopus (735) Google Scholar,2.Belin-Rauscent A. et al.How preclinical models evolved to resemble the diagnostic criteria of drug addiction.Biol. Psychiatry. 2015; 79: 39-46Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. The rapid development of new tools for neuronal and circuit measurement and manipulation has resulted in a better appreciation of the roles of different cells, brain regions, and circuits in behavioral control, including SUD-related behaviors. A natural next step is to combine the new information about these behavioral and neurobiological changes with the goal of developing new therapies for SUDs. This effort is timely and laudable but requires careful consideration of how brain circuitry is related to behavior. In the healthy waking animal, all parts of the brain receive information and are either active or poised to be active as needed to drive behaviors and adapt to changing circumstances. It is difficult to determine how global brain activity is related to behavior and thus neurobiologists usually attempt to assess which neurons, brain regions, and circuits dominate behavioral control (and cognition or affect in the human brain) at any given time. This approach often leads investigators to associate particular brain regions with specific behaviors, and the SUD field is not immune from this trap. Initially, such research begins with tasks designed and operationally defined to provide information about psychological constructs such as fear, anxiety, or substance craving. This approach generates ideas about the neural underpinnings of specific behaviors and explains these underpinnings in ways that are easy to grasp for those familiar with the behaviors. However, with time the findings are often interpreted as providing information about the neural basis of the entire psychological construct rather than the specific behaviors examined. Studies of the amygdala and fear provide an excellent case in point. Beautiful work in the 1990s by LeDoux and others [3.Ledoux J.E. Emotion circuits in the brain.Annu. Rev. Neurosci. 2000; 23: 155-184Crossref PubMed Scopus (5568) Google Scholar,4.Maren S. Fanselow M.S. The amygdala and fear conditioning: has the nut been cracked?.Neuron. 1996; 16: 237-240Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar] established that the activity and synaptic efficacy of amygdala neurons was altered during fear learning and extinction, while manipulation of amygdala function provided evidence that this brain region controls fear-related learning. These studies withstood the test of time and are being updated with valuable new ideas [5.Ledoux J.E. Pine D.S. Using neuroscience to help understand fear and anxiety: a two-system framework.Am. J. Psychiatry. 2016; 173: 1083-1093Crossref PubMed Scopus (261) Google Scholar]. This work also provided important information about amygdala complex functions. However, due in part to this line of research, there was a time when many neurobiologists equated the amygdala with fear and fear with the amygdala. Despite the usefulness of the research, this line of thinking had the dual negative effect of de-emphasizing other brain regions with important roles in fear-related behaviors and the larger role of the amygdala in value/valence coding for positive as well as negative outcomes [6.Fernando A.B.P. et al.The amygdala: securing pleasure and avoiding pain.Front. Behav. Neurosci. 2013; 7: 190Crossref PubMed Scopus (44) Google Scholar,7.Tye K.M. Neural circuit motifs in valence processing.Neuron. 2018; 100: 436-452Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. The idea that the amygdala may be a general arousal-based modulator of learning was also underappreciated [8.McGaugh J.L. The amygdala modulates the consolidation of memories of emotionally arousing experiences.Annu. Rev. Neurosci. 2004; 27: 1-28Crossref PubMed Scopus (1554) Google Scholar]. Clearly this was not the intent of the outstanding investigators studying fear conditioning circuitry, but largely the interpretation of neuroscientists from outside the field. For SUD-related research to avoid such overgeneralization, it is important to realize that brain regions, as part of complex circuits, are involved in multiple functions. It is also necessary to remember that psychological constructs arise from human verbal reports and are operationally defined in animal behavior studies, but do not necessarily correspond to the ways in which neural circuits control behavior. Thus, we would argue, it is important that neurobiologists attempt to understand brain activity, plasticity, and neuroadaptations independent of, and related to, in vivo measurements when evaluating the effects of abused substances. In the remainder of this review, we consider how this neurobiology-centric information approach can help investigators gain a better understanding of the effects of acute and chronic drug exposure in the context of the corticothalamo-basal ganglia (CTBG) circuitry. We suggest that focused 'bottom-up' approaches detailing how molecular and cellular functions contribute to circuit output in relation to defined in vivo phenotypes will provide a better understanding of how SUDs alter behavior. We also emphasize that consideration of divergent actions of different substances on neural function and behavior are important, and the relationship to the human condition must always be considered. The circuits involving the cortex, the thalamus, the basal ganglia, and the resultant outputs to the brainstem and back to the cortex are predominant anatomical and physiological motifs of the forebrain that have been reviewed extensively (Figure 1A ) [9.Reiner A.M. et al.Photophysics of diphenyl-pyrazole compounds in solutions and α-synuclein aggregates.Biochim. Biophys. Acta Gen. Subj. 2018; 1862: 800-807Crossref PubMed Scopus (5) Google Scholar,10.Yin H.H. Knowlton B.J. The role of the basal ganglia in habit formation.Nat. Rev. Neurosci. 2006; 7: 464-476Crossref PubMed Scopus (1350) Google Scholar]. Several such circuits exist, each with cortical and thalamic glutamatergic inputs to the striatum that drive the activity of medium spiny striatal projection neurons (MSNs) [11.Gerfen C.R. Bolam J.P. The neuroanatomical organization of the basal ganglia.Handb. Behav. Neurosci. 2010; 20: 3-28Crossref Scopus (56) Google Scholar]. While it has been tempting to view the CTBG circuits as providing a linear information flow with a binary net effect on the cortex and action production, this limited view of the circuits falls apart with only slightly deeper probing (Figure 1B). Furthermore, the linear concept of CTBG information flow does not capture the continuous processing and ongoing integration occurring within the circuits [12.Klaus A. et al.What, if, and when to move: basal ganglia circuits and self-paced action initiation.Annu. Rev. Neurosci. 2019; 42: 459-483Crossref PubMed Scopus (29) Google Scholar]. Clearly, there is much more to learn about CTBG circuits. Nonetheless, progress has been made in understanding how cortical input, striatal output, and net BG output influence behavior [11.Gerfen C.R. Bolam J.P. The neuroanatomical organization of the basal ganglia.Handb. Behav. 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Projections from the central amygdala to the lateral SNr may help to coordinate intercircuit communication [29.Haber S.N. Integrative networks across basal ganglia circuits.Handb. Behav. Neurosci. 2010; 20: 409-427Crossref Google Scholar] and are involved in action learning [30.Steinberg E.E. et al.A causal link between prediction errors, dopamine neurons and learning.Nat. Neurosci. 2013; 16: 966-973Crossref PubMed Scopus (426) Google Scholar]. Additional mechanisms of communication across CTBG circuits are likely to be discovered, raising the possibility that such circuit interactions contribute to altered in vivo phenotypes following the experience of and exposure to abused substances. One example that highlights the need to supplement psychological construct-based approaches with a circuit information-based approach comes from the focus in the SUD field on CTBG circuit contributions to habitual drug seeking and taking [31.Gremel C.M. Lovinger D.M. 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For example, based on the connectivity previously discussed, the caudate nucleus and other associative circuit components can respond to a combination of highly processed information about the environment combined with information about the likelihood, importance, and valence of sensory events and outcomes following actions. However, this information can be integrated with the sensorimotor circuit through thalamocortical, corticothalamic, and corticostriatal projections that cross the 'boundaries' of the traditional associative and sensorimotor loops [18.Hunnicutt B.J. et al.A comprehensive excitatory input map of the striatum reveals novel functional organization.Elife. 2016; 5e19103Crossref PubMed Scopus (124) Google Scholar,29.Haber S.N. Integrative networks across basal ganglia circuits.Handb. Behav. Neurosci. 2010; 20: 409-427Crossref Google Scholar,53.McFarland N.R. Haber S.N. 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