Abstract
Stress-linked disorders are more prevalent in women than in men and differ in their clinical presentation. Thus, investigating sex differences in factors that promote susceptibility or resilience to stress outcomes, and the circuit elements that mediate their effects, is important. In male rats, instrumental control over stressors engages a corticostriatal system involving the prelimbic cortex (PL) and dorsomedial striatum (DMS) that prevent many of the sequelae of stress exposure. Interestingly, control does not buffer against stress outcomes in females, and here, we provide evidence that the instrumental controlling response in females is supported instead by the dorsolateral striatum (DLS). Additionally, we used in vivo microdialysis, fluorescent in situ hybridization, and receptor subtype pharmacology to examine the contribution of prefrontal dopamine (DA) to the differential impact of behavioral control. Although both sexes preferentially expressed D1 receptor mRNA in PL GABAergic neurons, there were robust sex differences in the dynamic properties of prefrontal DA during controllable stress. Behavioral control potently attenuated stress-induced DA efflux in males, but not females, who showed a sustained DA increase throughout the entire stress session. Importantly, PL D1 receptor blockade (SCH 23390) shifted the proportion of striatal activity from the DLS to the DMS in females and produced the protective effects of behavioral control. These findings suggest a sex-selective mechanism in which elevated DA in the PL biases instrumental responding towards prefrontal-independent striatal circuitry, thereby eliminating the protective impact of coping with stress.
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References
Rubinow DR, Schmidt PJ. Sex differences and the neurobiology of affective disorders. Neuropsychopharmacology. 2019;44:111–28.
Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51:8–19.
Tolin DF, Foa EB. Sex differences in trauma and posttraumatic stress disorder: a quantitative review of 25 years of research. Psychol Bull. 2006;132:959–92.
Bandura A. Self-efficacy: The exercise of control. New York, NY, US: W H Freeman/Times Books/Henry Holt & Co; 1997.
Chorpita BF, Barlow DH. The development of anxiety: the role of control in the early environment. Psychol Bull. 1998;124:3–21.
Maier SF, Watkins LR. Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci Biobehav Rev. 2005;29:829–41.
Williams JL, Maier SF. Transituational immunization and therapy of learned helplessness in the rat. J Exp Psychol Anim Behav Process. 1977;3:240–52.
Amat J, Aleksejev RM, Paul E, Watkins LR, Maier SF. Behavioral control over shock blocks behavioral and neurochemical effects of later social defeat. Neuroscience. 2010;165:1031–8.
Baratta MV, Leslie NR, Fallon IP, Dolzani SD, Chun LE, Tamalunas AM, et al. Behavioural and neural sequelae of stressor exposure are not modulated by controllability in females. Eur J Neurosci. 2018;47:959–67.
Baratta MV, Gruene TM, Dolzani SD, Chun LE, Maier SF, Shansky RM. Controllable stress elicits circuit-specific patterns of prefrontal plasticity in males, but not females. Brain Struct Funct. 2019;224:1831–43.
Balleine BW, Liljeholm M, Ostlund SB. The integrative function of the basal ganglia in instrumental conditioning. Behav Brain Res. 2009;199:43–52.
Dickinson A, Balleine B. Motivational control of goal-directed action. Anim Learn Behav. 1994;22:1–18.
Yin HH, Knowlton BJ, Balleine BW. Lesions of dorsolateral striatum preserve outcome expectancy but disrupt habit formation in instrumental learning. Eur J Neurosci. 2004;19:181–9.
Smith KS, Graybiel AM. Habit formation. Dialogues Clin Neurosci. 2016;18:33–43.
Maier S, Seligman MEP, Solomon RL. Pavlovian fear conditioning and learned helplessness: Effects on escape and avoidance behavior of (a) the CS-US contingency, and (b) the independence of the US and voluntary responding. Punishment and aversive behavior. New York, NY: Appleton-Century-Crofts; 1969. p. 299–342.
Liljeholm M, Tricomi E, O’Doherty JP, Balleine BW. Neural correlates of instrumental contingency learning: differential effects of action–reward conjunction and disjunction. J Neurosci. 2011;31:2474–80.
Amat J, Christianson JP, Aleksejev RM, Kim J, Richeson KR, Watkins LR, et al. Control over a stressor involves the posterior dorsal striatum and the act/outcome circuit. Eur J Neurosci. 2014;40:2352–8.
Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci. 2005;8:365–71.
Amat J, Paul E, Zarza C, Watkins LR, Maier SF. Previous experience with behavioral control over stress blocks the behavioral and dorsal raphe nucleus activating effects of later uncontrollable stress: role of the ventral medial prefrontal cortex. J Neurosci. 2006;26:13264–72.
Arnsten AFT. Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci. 2009;10:410–22.
Arnsten AFT. Stress weakens prefrontal networks: molecular insults to higher cognition. Nat Neurosci. 2015;18:1376–85.
Christianson JP, Benison AM, Jennings J, Sandsmark EK, Amat J, Kaufman RD, et al. The sensory insular cortex mediates the stress-buffering effects of safety signals but not behavioral control. J Neurosci. 2008;28:13703–11.
Farovik A, Dupont LM, Arce M, Eichenbaum H. Medial prefrontal cortex supports recollection, but not familiarity, in the rat. J Neurosci. 2008;28:13428–34.
Sun W, Rebec GV. The role of prefrontal cortex D1-like and D2-like receptors in cocaine-seeking behavior in rats. Psychopharmacology. 2005;177:315–23.
Hall DA, Powers JP, Gulley JM. Blockade of D1 dopamine receptors in the medial prefrontal cortex attenuates amphetamine- and methamphetamine-induced locomotor activity in the rat. Brain Res. 2009;1300:51–57.
Gulledge AT, Jaffe DB. Multiple effects of dopamine on layer V pyramidal cell excitability in rat prefrontal cortex. J Neurophysiol. 2001;86:586–95.
De Mei C, Ramos M, Iitaka C, Borrelli E. Getting specialized: presynaptic and postsynaptic dopamine D2 receptors. Curr Opin Pharm. 2009;9:53–58.
Gulledge AT, Jaffe DB. Dopamine decreases the excitability of layer V pyramidal cells in the rat prefrontal cortex. J Neurosci. 1998;18:9139–51.
Tervo DGR, Hwang B-Y, Viswanathan S, Gaj T, Lavzin M, Ritola KD, et al. A designer AAV variant permits efficient retrograde access to projection neurons. Neuron. 2016;92:372–82.
Shepherd GMG. Corticostriatal connectivity and its role in disease. Nat Rev Neurosci. 2013;14:278–91.
Maier SF. Behavioral control blunts reactions to contemporaneous and future adverse events: medial prefrontal cortex plasticity and a corticostriatal network. Neurobiol Stress. 2015;1:12–22.
Balleine BW, O’Doherty JP. Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action. Neuropsychopharmacology. 2010;35:48–69.
Morris RW, Dezfouli A, Griffiths KR, Le Pelley ME, Balleine BW. The neural bases of action-outcome learning in humans. J Neurosci. 2022;42:3636–47.
Corbit LH, Muir JL, Balleine BW. Lesions of mediodorsal thalamus and anterior thalamic nuclei produce dissociable effects on instrumental conditioning in rats. Eur J Neurosci. 2003;18:1286–94.
Yin HH, Knowlton BJ. The role of the basal ganglia in habit formation. Nat Rev Neurosci. 2006;7:464–76.
Schoenberg HL, Sola EX, Seyller E, Kelberman M, Toufexis DJ. Female rats express habitual behavior earlier in operant training than males. Behav Neurosci. 2019;133:110–20.
Schoenberg HL, Bremer GP, Carasi-Schwartz F, VonDoepp S, Arntsen C, Anacker AMJ, et al. Cyclic estrogen and progesterone during instrumental acquisition contributes to habit formation in female rats. Horm Behav. 2022;142:105172.
Wingard JC, Packard MG. The amygdala and emotional modulation of competition between cognitive and habit memory. Behav Brain Res. 2008;193:126–31.
Shiflett MW, Balleine BW. Molecular substrates of action control in cortico-striatal circuits. Prog Neurobiol. 2011;95:1–13.
Hart G, Bradfield LA, Balleine BW. Prefrontal corticostriatal disconnection blocks the acquisition of goal-directed action. J Neurosci. 2018;38:1311–22.
Hart G, Bradfield LA, Fok SY, Chieng B, Balleine BW. The bilateral prefronto-striatal pathway is necessary for learning new goal-directed actions. Curr Biol. 2018;28:2218–29.e7.
Murphy BL, Arnsten AFT, Jentsch JD, Roth RH. Dopamine and spatial working memory in rats and monkeys: pharmacological reversal of stress-induced impairment. J Neurosci. 1996;16:7768–75.
Murphy BL, Arnsten AF, Goldman-Rakic PS, Roth RH. Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. Proc Natl Acad Sci. 1996;93:1325–9.
Arnsten AF, Dudley AG. Methylphenidate improves prefrontal cortical cognitive function through α2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder. Behav Brain Funct. 2005;1:2.
Aston-Jones G, Cohen JD. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci. 2005;28:403–50.
Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, Cerqueira JJ, et al. Chronic stress causes frontostriatal reorganization and affects decision-making. Science. 2009;325:621–5.
Taylor SB, Anglin JM, Paode PR, Riggert AG, Olive MF, Conrad CD. Chronic stress may facilitate the recruitment of habit- and addiction-related neurocircuitries through neuronal restructuring of the striatum. Neuroscience. 2014;280:231–42.
Gamo NJ, Lur G, Higley MJ, Wang M, Paspalas CD, Vijayraghavan S, et al. Stress impairs prefrontal cortical function via D1 dopamine receptor interactions with hyperpolarization-activated cyclic nucleotide-gated channels. Biol Psychiatry. 2015;78:860–70.
Mitsushima D, Yamada K, Takase K, Funabashi T, Kimura F. Sex differences in the basolateral amygdala: the extracellular levels of serotonin and dopamine, and their responses to restraint stress in rats. Eur J Neurosci. 2006;24:3245–54.
Heinsbroek RPW, Van Haaren F, Feenstra MGP, Endert E, Van de Poll NE. Sex- and time-dependent changes in neurochemical and hormonal variables induced by predictable and unpredictable footshock. Physiol Behav. 1991;49:1251–6.
McDevitt RA, Szot P, Baratta MV, Bland ST, White SS, Maier SF, et al. Stress-induced activity in the locus coeruleus is not sensitive to stressor controllability. Brain Res. 2009;1285:109–18.
Rivera-Garcia MT, McCane AM, Chowdhury TG, Wallin-Miller KG, Moghaddam B. Sex and strain differences in dynamic and static properties of the mesolimbic dopamine system. Neuropsychopharmacology. 2020;45:2079–86.
Zachry JE, Nolan SO, Brady LJ, Kelly SJ, Siciliano CA, Calipari ES. Sex differences in dopamine release regulation in the striatum. Neuropsychopharmacology. 2021;46:491–9.
Kritzer MF, Creutz LM. Region and sex differences in constituent dopamine neurons and immunoreactivity for intracellular estrogen and androgen receptors in mesocortical projections in rats. J Neurosci. 2008;28:9525–35.
Santana N, Mengod G, Artigas F. Quantitative analysis of the expression of dopamine D1 and D2 receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb Cortex. 2009;19:849–60.
Gorelova N, Seamans JK, Yang CR. Mechanisms of dopamine activation of fast-spiking interneurons that exert inhibition in rat prefrontal cortex. J Neurophysiol. 2002;88:3150–66.
Seamans JK, Gorelova N, Durstewitz D, Yang CR. Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci. 2001;21:3628–38.
Tseng KY, O’Donnell P. Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. J Neurosci. 2004;24:5131–9.
Dreyer JK, Herrik KF, Berg RW, Hounsgaard JD. Influence of phasic and tonic dopamine release on receptor activation. J Neurosci. 2010;30:14273–83.
Martel JC, Gatti McArthur S. Dopamine receptor subtypes, physiology and pharmacology: new ligands and concepts in schizophrenia. Front Pharmacol. 2020;11:1003.
McGeorge AJ, Faull RL. The organization of the projection from the cerebral cortex to the striatum in the rat. Neuroscience. 1989;29:503–37.
Smith KS, Graybiel AM. A dual operator view of habitual behavior reflecting cortical and striatal dynamics. Neuron. 2013;79:361–74.
Killcross S, Coutureau E. Coordination of actions and habits in the medial prefrontal cortex of rats. Cereb Cortex. 2003;13:400–8.
Barker JM, Glen WB, Linsenbardt DN, Lapish CC, Chandler LJ. Habitual behavior is mediated by a shift in response-outcome encoding by infralimbic cortex. ENeuro. 2017;4:ENEURO.0337-17.2017.
Coutureau E, Killcross S. Inactivation of the infralimbic prefrontal cortex reinstates goal-directed responding in overtrained rats. Behav Brain Res. 2003;146:167–74.
Smith KS, Virkud A, Deisseroth K, Graybiel AM. Reversible online control of habitual behavior by optogenetic perturbation of medial prefrontal cortex. Proc Natl Acad Sci. 2012;109:18932–7.
Barker JM, Torregrossa MM, Taylor JR. Bidirectional modulation of infralimbic dopamine D1 and D2 receptor activity regulates flexible reward seeking. Front Neurosci. 2013;7:126.
Acknowledgements
The authors would like to thank Dr. James Orth and the Light Microscopy Core Facility at the University of Colorado Boulder (RRID:SCR_018993) for their support.
Funding
This work was supported by National Institutes of Health grants R01 MH050479 (SFM), R21 MH116353 (MVB), R01 DA047443 (DHR), and NARSAD Young Investigator Grants from the Brain and Behavior Research Foundation (MVB, DHR).
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SFM and MVB conceived and designed the experiments. CJM, IPF, JA, RJS, NRL, DHR, and MVB performed the experiments and analyzed the data. CJM and MVB wrote the manuscript. All authors provided feedback on the manuscript.
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McNulty, C.J., Fallon, I.P., Amat, J. et al. Elevated prefrontal dopamine interferes with the stress-buffering properties of behavioral control in female rats. Neuropsychopharmacol. 48, 498–507 (2023). https://doi.org/10.1038/s41386-022-01443-w
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DOI: https://doi.org/10.1038/s41386-022-01443-w
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