Insular neural system controls decision-making in healthy and methamphetamine-treated rats

Abstract

Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders exhibit altered decisionmaking patterns, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using a gambling test, we demonstrated that methamphetamine (METH)-treated rats chose a highrisk/high-reward option more frequently and assigned higher value to high returns than control rats, suggestive of changes in decisionmaking choice strategy. Immunohistochemical analysis following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-treated animals. Pharmacological studies, together with in vivo microdialysis, showed that the insular neural system played a crucial role in decision-making. Moreover, manipulation of INS activation using designer receptor exclusively activated by designer drug technology resulted in alterations to decision-making. Our findings suggest that the INS is a critical region involved in decision-making and that insular neural dysfunction results in risk-taking behaviors associated with altered decision-making.decision-making | methamphetamine | insular cortex | DREADD | motivational value D ecision-making is a key activity of everyday life. Consequently, disturbances in the ability to make appropriate decisions or anticipate their possible consequences can result in massive social, medical, and financial problems. Decision-making depends on three temporally and partially functionally distinct sets of processes: (i) assessment and formation of preferences among possible options, (ii) selection and execution of an action, and (iii) experience or evaluation of the outcome (1). These processes are thought to require an extended neural network, mainly comprising glutamatergic, serotonergic, noradrenergic, and dopaminergic pathways in the frontostriatal and limbic loops, including the cingulate cortex, orbitofrontal cortex (OFC), insular cortex (INS), striatum (St), basal ganglia, and amygdala (2). Analysis of these processes helps to distinguish which aspects of decision-making are differentially affected in various neuropsychiatric disorders (1).Poor decision-making is a symptom of several neuropsychiatric diseases, such as depression, schizophrenia, Parkinson's disease, and drug dependence (1,(3)(4)(5). Pathological decision-making in neuropsychiatric disorders is associated with an inability to make profitable long-term decisions that incorporate expectations of future outcomes (6). Thus, pathological decision-making is recognized as a core problem in neuropsychiatric disorders, and a better understanding of the mechanisms underlying altered decisionmaking should provide insights that could lead to successful treatments for these diseases.A hallmark of addiction is continuous use of substances despite negative consequences or the absence of positive consequences (7). Addicts are less able to flexibly adapt their behavior to changes in reward contingenci...

The anterior insula bidirectionally modulates cost‐benefit decision‐making on a rodent gambling task

“…In the present study, bilateral lesions of the AIC may have prevented the retrieval of the subjective incentive value of the different options prior to response selection, leading to alterations in responding in animals that had previously expressed strong preferences between risky and safe options. Such an explanation may also be helpful in elucidating the conflicting data from previous studies using other operationalized versions of the IGT in rodents, in which manipulations of the insula were observed to either increase (Mizoguchi et al ., ) or decrease (Pushparaj et al ., ) risky choice. These studies utilized different behavioural paradigms, but both temporarily silenced the insula, through either pharmacological or chemogenetic methods and importantly, in both examples, either the safe (Pushparaj et al ., ) or risky (Mizoguchi et al ., ) options were selected relatively infrequently at baseline prior to AIC inactivation.…”

“…Previous studies utilizing different rodent versions of the IGT have further suggested an involvement of the insula in cost‐benefit decision‐making, although the results are equivocal. AIC lesions and inactivations increased choice of smaller more certain rewards in one study (Pushparaj et al ., ), whereas chemogenetic inhibition of the insula increased choice of a high‐risk high reward option, using a maze based task (Mizoguchi et al ., ). However, both of these paradigms utilized relatively extensive training regimes and did not address the potential contribution of the AIC to inter‐individual differences in decision‐making.…”

Clozapine N-Oxide Administration Produces Behavioral Effects in Long–Evans Rats: Implications for Designing DREADD Experiments

“…Control injections were 0.5% DMSO in saline solution. Of the 22 articles that we found that used systemic administration of CNO in rats (Ferguson et al, 2011, 2013; Anderson et al, 2013; Michaelides et al, 2013; Boender et al, 2014; Bull et al, 2014; Dell’Anno et al, 2014; Kätzel et al, 2014; Robinson et al, 2014; Chang et al, 2015; Gompf et al, 2015; Mizoguchi et al, 2015; Pienaar et al, 2015; Scofield et al, 2015; Yau and McNally, 2015; Grace et al, 2016; Ma et al, 2016; Marchant et al, 2016; Qiu et al, 2016; Sengupta et al, 2016; Wicker and Forcelli, 2016; Wirtshafter and Stratford, 2016), 2 used chronic treatment (e.g., in drinking water) and 11 used doses >1 mg/kg. Of those that used doses of >1 mg/kg, most used doses of 3 mg/kg, but in a few cases doses were as high as 10 mg/kg.…”

“…In this design, it is impossible to separate out the effects of activation of the DREADD from any unexpected effects of CNO, which could be the enhancement or blockade of the expected result of DREADD activation. In terms of dosing, a wide range of doses (0.2–10 mg/kg) is regularly used in DREADD experiments (Alexander et al, 2009; Ferguson et al, 2011, 2013; Ray et al, 2011; Agulhon et al, 2013; Anderson et al, 2013; Farrell et al, 2013; Michaelides et al, 2013; Wang et al, 2013; Boender et al, 2014; Bull et al, 2014; Dell’Anno et al, 2014; Kätzel et al, 2014; Robinson et al, 2014; Zhu et al, 2014; Chang et al, 2015; Gompf et al, 2015; Mizoguchi et al, 2015; Pienaar et al, 2015; Scofield et al, 2015; Yau and McNally, 2015; Grace et al, 2016; Ma et al, 2016; Marchant et al, 2016; Qiu et al, 2016; Sengupta et al, 2016; Wicker and Forcelli, 2016), and there is seldom any explanation given as to how the dose that was used was decided upon. Using the lowest effectual dose in the assay to be performed, that which in the non-DREADD-expressing animals is experimentally silent, would seem the most straightforward way to minimize any off-target effects of CNO.…”

DREADDS: Use and application in behavioral neuroscience.

“…Both of these studies employed DREADDs to support the notion that MSNs in thee D1 direct-pathway, and D2 indirect-pathway, play a crucial role in activating, and inhibiting, reward-related locomotor activation. Also related to the influence of psychostimulants on neuronal function, Mizoguchi et al (Mizoguchi et al, 2015) found using hM4Di and hM3Dq DREADDs that risky behavior in a rat gambling task involved insular cortex, as does methamphetamine-induced increases in risky behavior.…”