Abstract
Prefrontal cortex (PFC) maturation during adolescence is characterized by structural and functional changes, which involve the remodeling of GABA and glutamatergic synapses, as well as changes in the endocannabinoid system. Yet, the way PFC endocannabinoid signaling interacts with local GABA and glutamatergic function to impact its processing of afferent transmission during the adolescent transition to adulthood remains unknown. Here we combined PFC local field potential recordings with local manipulations of 2-AG and anandamide levels to assess how PFC endocannabinoid signaling is recruited to modulate ventral hippocampal and basolateral amygdalar inputs in vivo in adolescent and adult male rats. We found that the PFC endocannabinoid signaling does not fully emerge until late-adolescence/young adulthood. Once present, both 2-AG and anandamide can be recruited in the PFC to limit the impact of hippocampal drive through a CB1R-mediated mechanism whereas basolateral amygdalar inputs are only inhibited by 2-AG. Similarly, the behavioral effects of increasing 2-AG and anandamide in the PFC do not emerge until late-adolescence/young adulthood. Using a trace fear conditioning paradigm, we found that elevating PFC 2-AG levels preferentially reduced freezing behavior during acquisition without affecting its extinction. In contrast, increasing anandamide levels in the PFC selectively disrupted the extinction of trace fear memory without affecting its acquisition. Collectively, these results indicate a protracted recruitment of PFC endocannabinoid signaling, which becomes online in late adolescence/young adulthood as revealed by its impact on hippocampal and amygdalar-evoked local field potential responses and trace fear memory behavior.
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All data supporting the conclusions of this manuscript will be made available to any qualified researcher without undue reservation.
References
Best JR, Miller PH. A developmental perspective on executive function. Child Dev. 2010;81:1641–60.
Caballero A, Granberg R, Tseng KY. Mechanisms contributing to prefrontal cortex maturation during adolescence. Neurosci Biobehav Rev. 2016;70:4–12.
Caballero A, Tseng KY. GABAergic function as a limiting factor for prefrontal maturation during adolescence. Trends Neurosci. 2016;39:441–8.
Casey BJ, Giedd JN, Thomas KM. Structural and functional brain development and its relation to cognitive development. Biol Psychol. 2000;54:241–57.
Tseng KY, Chambers RA, Lipska BK. The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia. Behav Brain Res. 2009;204:295–305.
Yang S, Tseng KY. Maturation of corticolimbic functional connectivity during sensitive periods of brain development. Curr Top Behav Neurosci. 2022;53:37–53.
Garcia R, Vouimba RM, Baudry M, Thompson RF. The amygdala modulates prefrontal cortex activity relative to conditioned fear. Nature. 1999;402:294–6.
Hariri AR, Mattay VS, Tessitore A, Fera F, Weinberger DR. Neocortical modulation of the amygdala response to fearful stimuli. Biol Psychiatry. 2003;53:494–501.
Tse MT, Piantadosi PT, Floresco SB. Prefrontal cortical gamma-aminobutyric acid transmission and cognitive function: drawing links to schizophrenia from preclinical research. Biol Psychiatry. 2015;77:929–39.
Wang GW, Cai JX. Disconnection of the hippocampal-prefrontal cortical circuits impairs spatial working memory performance in rats. Behav Brain Res. 2006;175:329–36.
Caballero A, Thomases DR, Flores-Barrera E, Cass DK, Tseng KY. Emergence of GABAergic-dependent regulation of input-specific plasticity in the adult rat prefrontal cortex during adolescence. Psychopharmacology. 2014;231:1789–96.
Flores-Barrera E, Thomases DR, Heng LJ, Cass DK, Caballero A, Tseng KY. Late adolescent expression of GluN2B transmission in the prefrontal cortex is input-specific and requires postsynaptic protein kinase A and D1 dopamine receptor signaling. Biol Psychiatry. 2014;75:508–16.
Cass DK, Thomases DR, Caballero A, Tseng KY. Developmental disruption of gamma-aminobutyric acid function in the medial prefrontal cortex by noncontingent cocaine exposure during early adolescence. Biol Psychiatry. 2013;74:490–501.
Thomases DR, Cass DK, Tseng KY. Periadolescent exposure to the NMDA receptor antagonist MK-801 impairs the functional maturation of local GABAergic circuits in the adult prefrontal cortex. J Neurosci. 2013;33:26–34.
Caballero A, Orozco A, Tseng KY. Developmental regulation of excitatory-inhibitory synaptic balance in the prefrontal cortex during adolescence. Semin Cell Dev Biol. 2021;118:60–3.
Ellgren M, Artmann A, Tkalych O, Gupta A, Hansen HS, Hansen SH, et al. Dynamic changes of the endogenous cannabinoid and opioid mesocorticolimbic systems during adolescence: THC effects. Eur Neuropsychopharmacol. 2008;18:826–34.
Heng L, Beverley JA, Steiner H, Tseng KY. Differential developmental trajectories for CB1 cannabinoid receptor expression in limbic/associative and sensorimotor cortical areas. Synapse. 2011;65:278–86.
Lee TT, Hill MN, Hillard CJ, Gorzalka BB. Temporal changes in N-acylethanolamine content and metabolism throughout the peri-adolescent period. Synapse. 2013;67:4–10.
Meyer HC, Lee FS, Gee DG. The role of the endocannabinoid system and genetic variation in adolescent brain development. Neuropsychopharmacology. 2018;43:21–33.
Kreitzer AC, Regehr WG. Retrograde signaling by endocannabinoids. Curr Opin Neurobiol. 2002;12:324–30.
Caballero A, Tseng KY. Association of cannabis use during adolescence, prefrontal Cb1 receptor signaling, and schizophrenia. Front Pharmacol. 2012;3:101.
Molla HM, Tseng KY. Neural substrates underlying the negative impact of cannabinoid exposure during adolescence. Pharmacol Biochem Behav. 2020;195:172965.
Gilmartin MR, Balderston NL, Helmstetter FJ. Prefrontal cortical regulation of fear learning. Trends Neurosci. 2014;37:455–64.
Gilmartin MR, Kwapis JL, Helmstetter FJ. Trace and contextual fear conditioning are impaired following unilateral microinjection of muscimol in the ventral hippocampus or amygdala, but not the medial prefrontal cortex. Neurobiol Learn Mem. 2012;97:452–64.
Ishikawa A, Nakamura S. Convergence and interaction of hippocampal and amygdalar projections within the prefrontal cortex in the rat. J Neurosci. 2003;23:9987–95.
Sierra-Mercado D, Padilla-Coreano N, Quirk GJ. Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear. Neuropsychopharmacology. 2011;36:529–38.
Sotres-Bayon F, Sierra-Mercado D, Pardilla-Delgado E, Quirk GJ. Gating of fear in prelimbic cortex by hippocampal and amygdala inputs. Neuron. 2012;76:804–12.
Caballero A, Flores-Barrera E, Thomases DR, Tseng KY. Downregulation of parvalbumin expression in the prefrontal cortex during adolescence causes enduring prefrontal disinhibition in adulthood. Neuropsychopharmacology. 2020;45:1527–35.
Flores-Barrera E, Thomases DR, Tseng KY. MK-801 exposure during adolescence elicits enduring disruption of prefrontal E-I balance and its control of fear extinction behavior. J Neurosci. 2020;40:4881–7.
Miguelez Fernández AMM, Molla HM, Thomases DR, Tseng KY. Prefrontal alpha7nAChR signaling differentially modulates afferent drive and trace fear conditioning behavior in adolescent and adult rats. J Neurosci. 2021;41:1908–16.
Thomases DR, Cass DK, Meyer JD, Caballero A, Tseng KY. Early adolescent MK-801 exposure impairs the maturation of ventral hippocampal control of basolateral amygdala drive in the adult prefrontal cortex. J Neurosci. 2014;34:9059–66.
Lew SE, Tseng KY. Dopamine modulation of GABAergic function enables network stability and input selectivity for sustaining working memory in a computational model of the prefrontal cortex. Neuropsychopharmacology. 2014;39:3067–76.
Van Waes V, Beverley JA, Siman H, Tseng KY, Steiner H. CB1 cannabinoid receptor expression in the striatum: association with corticostriatal circuits and developmental regulation. Front Pharmacol. 2012;3:21.
Fitzgerald ML, Mackie K, Pickel VM. Ultrastructural localization of cannabinoid CB1 and mGluR5 receptors in the prefrontal cortex and amygdala. J Comp Neurol. 2019;527:2730–41.
Lafourcade M, Elezgarai I, Mato S, Bakiri Y, Grandes P, Manzoni OJ. Molecular components and functions of the endocannabinoid system in mouse prefrontal cortex. PLoS ONE. 2007;2:e709.
Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA. 2002;99:10819–24.
Gulyas AI, Cravatt BF, Bracey MH, Dinh TP, Piomelli D, Boscia F, et al. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci. 2004;20:441–58.
Egertová M, Giang DK, Cravatt BF, Elphick MR. A new perspective on cannabinoid signalling: complementary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain. Proc Biol Sci. 1998;265:2081–5.
Tsou K, Nogueron MI, Muthian S, Sañudo-Pena MC, Hillard CJ, Deutsch DG, et al. Fatty acid amide hydrolase is located preferentially in large neurons in the rat central nervous system as revealed by immunohistochemistry. Neurosci Lett. 1998;254:137–40.
Kucera R, Bouskila J, Elkrief L, Fink-Jensen A, Palmour R, Bouchard JF, et al. Expression and localization of CB1R, NAPE-PLD, and FAAH in the vervet monkey nucleus accumbens. Sci Rep. 2018;8:8689.
Laviolette SR, Grace AA. Cannabinoids potentiate emotional learning plasticity in neurons of the medial prefrontal cortex through basolateral amygdala inputs. J Neurosci. 2006;26:6458–68.
Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature. 2002;418:530–4.
Reich CG, Mohammadi MH, Alger BE. Endocannabinoid modulation of fear responses: learning and state-dependent performance effects. J Psychopharmacol. 2008;22:769–77.
Tan H, Lauzon NM, Bishop SF, Bechard MA, Laviolette SR. Integrated cannabinoid CB1 receptor transmission within the amygdala-prefrontal cortical pathway modulates neuronal plasticity and emotional memory encoding. Cereb Cortex. 2010;20:1486–96.
Gilmartin MR, Helmstetter FJ. Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex. Learn Mem. 2010;17:289–96.
Gilmartin MR, Kwapis JL, Helmstetter FJ. NR2A- and NR2B-containing NMDA receptors in the prelimbic medial prefrontal cortex differentially mediate trace, delay, and contextual fear conditioning. Learn Mem. 2013;20:290–4.
Courtin J, Chaudun F, Rozeske RR, Karalis N, Gonzalez-Campo C, Wurtz H, et al. Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature. 2014;505:92–6.
Sparta DR, Hovelsø N, Mason AO, Kantak PA, Ung RL, Decot HK, et al. Activation of prefrontal cortical parvalbumin interneurons facilitates extinction of reward-seeking behavior. J Neurosci. 2014;34:3699–705.
Patel S, Hill MN, Cheer JF, Wotjak CT, Holmes A. The endocannabinoid system as a target for novel anxiolytic drugs. Neurosci Biobehav Rev. 2017;76:56–66.
Rubino T, Realini N, Castiglioni C, Guidali C, Viganó D, Marras E, et al. Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex. Cereb Cortex. 2008;18:1292–301.
Cass DK, Flores-Barrera E, Thomases DR, Vital WF, Caballero A, Tseng KY. CB1 cannabinoid receptor stimulation during adolescence impairs the maturation of GABA function in the adult rat prefrontal cortex. Mol Psychiatry. 2014;19:536–43.
Funding
Supported by NIH Grants (R01-MH086507, R01-MH105488, R01-DA056447 to KYT) and Institutional startup funds from the College of Medicine – University of Illinois Chicago to KYT.
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Hanna M. Molla and Kuei Y. Tseng designed the study, wrote the manuscript, and prepared the figures. Hanna M. Molla performed all electrophysiological and behavioral experiments and data analyses under the supervision of Kuei Y. Tseng. Anabel M. M. Miguelez Fernández assisted Hanna M. Molla with the execution of the behavioral experiments.
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Molla, H.M., Miguelez Fernández, A.M.M. & Tseng, K.Y. Late-adolescent onset of prefrontal endocannabinoid control of hippocampal and amygdalar inputs and its impact on trace-fear conditioning behavior. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01844-z
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DOI: https://doi.org/10.1038/s41386-024-01844-z