Abstract
Children exposed to neglect or social deprivation are at heightened risk for psychiatric disorders and abnormal social patterns as adults. There is also evidence that prepubertal neglect in children causes abnormal metabolic activity in several brain regions, including the amygdala area. The medial nucleus of the amygdala (MeA) is a key region for performance of social behaviors and still undergoes maturation during the periadolescent period. As such, the normal development of this region may be disrupted by social deprivation. In rodents, postweaning social isolation causes a range of deficits in sexual and agonistic behaviors that normally rely on the posterior MeA (MeAp). However, little is known about the effects of social isolation on the function of MeA neurons. In this study, we tested whether postweaning social isolation caused abnormal activity of MeA neurons. We found that postweaning social isolation caused a decrease of in vivo firing activity of MeAp neurons, and reduced drive from excitatory afferents. In vitro electrophysiological studies found that postweaning social isolation caused a presynaptic impairment of excitatory input to the dorsal MeAp, but a progressive postsynaptic reduction of membrane excitability in the ventral MeAp. These results demonstrate discrete, subnucleus-specific effects of social deprivation on the physiology of MeAp neurons. This pathophysiology may contribute to the disruption of social behavior after developmental social deprivation, and may be a novel target to facilitate the treatment of social disorders.
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References
Adolphs R, Gosselin F, Buchanan TW, Tranel D, Schyns P, Damasio AR (2005). A mechanism for impaired fear recognition after amygdala damage. Nature 433: 68–72.
Adolphs R, Tranel D, Damasio H, Damasio A (1994). Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature 372: 669–672.
Agis-Balboa RC, Pinna G, Pibiri F, Kadriu B, Costa E, Guidotti A (2007). Down-regulation of neurosteroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice. Proc Natl Acad Sci USA 104: 18736–18741.
Ahern M, Goodell DJ, Adams J, Bland ST (2016). Brain regional differences in social encounter-induced Fos expression in male and female rats after post-weaning social isolation. Brain Res 1630: 120–133.
Ashwin C, Wheelwright S, Baron-Cohen S (2006). Finding a face in the crowd: testing the anger superiority effect in Asperger syndrome. Brain Cogn 61: 78–95.
Bakker J, van Ophemert J, Slob AK (1995). Postweaning housing conditions and partner preference and sexual behavior of neonatally ATD-treated male rats. Psychoneuroendocrinology 20: 299–310.
Bakshi VP, Geyer MA (1999). Ontogeny of isolation rearing-induced deficits in sensorimotor gating in rats. Physiol Behav 67: 385–392.
Baron-Cohen S, Ring HA, Wheelwright S, Bullmore ET, Brammer MJ, Simmons A et al (1999). Social intelligence in the normal and autistic brain: an fMRI study. Eur J Neurosci 11: 1891–1898.
Bergan JF, Ben-Shaul Y, Dulac C (2014). Sex-specific processing of social cues in the medial amygdala. Elife 3: e02743.
Bian X, Yanagawa Y, Chen WR, Luo M (2008). Cortical-like functional organization of the pheromone-processing circuits in the medial amygdala. J Neurophysiol 99: 77–86.
Breiter HC, Etcoff NL, Whalen PJ, Kennedy WA, Rauch SL, Buckner RL et al (1996). Response and habituation of the human amygdala during visual processing of facial expression. Neuron 17: 875–887.
Chareyron LJ, Lavenex PB, Lavenex P (2012). Postnatal development of the amygdala: a stereological study in rats. J Comp Neurol 520: 3745–3763.
Choi GB, Dong HW, Murphy AJ, Valenzuela DM, Yancopoulos GD, Swanson LW et al (2005). Lhx6 delineates a pathway mediating innate reproductive behaviors from the amygdala to the hypothalamus. Neuron 46: 647–660.
Coccaro EF, McCloskey MS, Fitzgerald DA, Phan KL (2007). Amygdala and orbitofrontal reactivity to social threat in individuals with impulsive aggression. Biol Psychiatry 62: 168–178.
Cooke BM (2006). Steroid-dependent plasticity in the medial amygdala. Neuroscience 138: 997–1005.
Cooke BM (2011). Synaptic reorganisation of the medial amygdala during puberty. J Neuroendocrinol 23: 65–73.
Cooke BM, Chowanadisai W, Breedlove SM (2000). Post-weaning social isolation of male rats reduces the volume of the medial amygdala and leads to deficits in adult sexual behavior. Behav Brain Res 117: 107–113.
Critchley HD, Daly EM, Bullmore ET, Williams SC, Van Amelsvoort T, Robertson DM et al (2000). The functional neuroanatomy of social behaviour: changes in cerebral blood flow when people with autistic disorder process facial expressions. Brain 123: 2203–2212.
Davis FC, Johnstone T, Mazzulla EC, Oler JA, Whalen PJ (2010). Regional response differences across the human amygdaloid complex during social conditioning. Cereb Cortex 20: 612–621.
De Lorme KC, Schulz KM, Salas-Ramirez KY, Sisk CL (2012). Pubertal testosterone organizes regional volume and neuronal number within the medial amygdala of adult male Syrian hamsters. Brain Res 1460: 33–40.
DiBenedictis BT, Olugbemi AO, Baum MJ, Cherry JA (2015). DREADD-induced silencing of the medial olfactory tubercle disrupts the preference of female mice for opposite-sex chemosignals. eNeuro 2, pii: ENEURO.0078-15.2015.
Einon DF, Humphreys AP, Chivers SM, Field S, Naylor V (1981). Isolation has permanent effects upon the behavior of the rat, but not the mouse, gerbil, or guinea pig. Dev Psychobiol 14: 343–355.
Fagiolini M, Pizzorusso T, Berardi N, Domenici L, Maffei L (1994). Functional postnatal development of the rat primary visual cortex and the role of visual experience: dark rearing and monocular deprivation. Vision Res 34: 709–720.
Ferdman N, Murmu RP, Bock J, Braun K, Leshem M (2007). Weaning age, social isolation, and gender, interact to determine adult explorative and social behavior, and dendritic and spine morphology in prefrontal cortex of rats. Behav Brain Res 180: 174–182.
Fleming AS, Suh EJ, Korsmit M, Rusak B (1994). Activation of Fos-like immunoreactivity in the medial preoptic area and limbic structures by maternal and social interactions in rats. Behav Neurosci 108: 724–734.
Fleming AS, Walsh C (1994). Neuropsychology of maternal behavior in the rat: c-fos expression during mother-litter interactions. Psychoneuroendocrinology 19: 429–443.
Fried I, Cameron KA, Yashar S, Fong R, Morrow JW (2002). Inhibitory and excitatory responses of single neurons in the human medial temporal lobe during recognition of faces and objects. Cereb Cortex 12: 575–584.
Fried I, MacDonald KA, Wilson CL (1997). Single neuron activity in human hippocampus and amygdala during recognition of faces and objects. Neuron 18: 753–765.
Gadziola MA, Grimsley JM, Shanbhag SJ, Wenstrup JJ (2012). A novel coding mechanism for social vocalizations in the lateral amygdala. J Neurophysiol 107: 1047–1057.
Gerall HD, Ward IL, Gerall AA (1967). Disruption of the male rat’s sexual behaviour induced by social isolation. Anim Behav 15: 54–58.
Gilabert-Juan J, Molto MD, Nacher J (2012). Post-weaning social isolation rearing influences the expression of molecules related to inhibitory neurotransmission and structural plasticity in the amygdala of adult rats. Brain Res 1448: 129–136.
Gordon JA, Stryker MP (1996). Experience-dependent plasticity of binocular responses in the primary visual cortex of the mouse. J Neurosci 16: 3274–3286.
Gos T, Becker K, Bock J, Malecki U, Bogerts B, Poeggel G et al (2006). Early neonatal and postweaning social emotional deprivation interferes with the maturation of serotonergic and tyrosine hydroxylase-immunoreactive afferent fiber systems in the rodent nucleus accumbens, hippocampus and amygdala. Neuroscience 140: 811–821.
Grady CL, Keightley ML (2002). Studies of altered social cognition in neuropsychiatric disorders using functional neuroimaging. Can J Psychiatry 47: 327–336.
Hall FS, Huang S, Fong GW, Pert A, Linnoila M (1998). Effects of isolation-rearing on voluntary consumption of ethanol, sucrose and saccharin solutions in Fawn Hooded and Wistar rats. Psychopharmacology (Berl) 139: 210–216.
Hall FS, Humby T, Wilkinson LS, Robbins TW (1997). The effects of isolation-rearing of rats on behavioural responses to food and environmental novelty. Physiol Behav 62: 281–290.
Helmeke C, Ovtscharoff WJ, Poeggel G, Braun K (2001). Juvenile emotional experience alters synaptic inputs on pyramidal neurons in the anterior cingulate cortex. Cereb Cortex 11: 717–727.
Hoffman KL, Gothard KM, Schmid MC, Logothetis NK (2007). Facial-expression and gaze-selective responses in the monkey amygdala. Curr Biol 17: 766–772.
Hol T, Van den Berg CL, Van Ree JM, Spruijt BM (1999). Isolation during the play period in infancy decreases adult social interactions in rats. Behav Brain Res 100: 91–97.
Hong W, Kim DW, Anderson DJ (2014). Antagonistic control of social versus repetitive self-grooming behaviors by separable amygdala neuronal subsets. Cell 158: 1348–1361.
Hubel DH, Wiesel TN, LeVay S (1977). Plasticity of ocular dominance columns in monkey striate cortex. Philos Trans R Soc Lond Ser B 278: 377–409.
Ichikawa M, Matsuoka M, Mori Y (1993). Effect of differential rearing on synapses and soma size in rat medial amygdaloid nucleus. Synapse 13: 50–56.
Ikemoto S, Panksepp J (1992). The effects of early social isolation on the motivation for social play in juvenile rats. Dev Psychobiol 25: 261–274.
Jeon D, Kim S, Chetana M, Jo D, Ruley HE, Lin SY et al (2010). Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC. Nat Neurosci 13: 482–488.
Jones AP, Laurens KR, Herba CM, Barker GJ, Viding E (2009). Amygdala hypoactivity to fearful faces in boys with conduct problems and callous-unemotional traits. Am J Psychiatry 166: 95–102.
Kang N, Baum MJ, Cherry JA (2009). A direct main olfactory bulb projection to the 'vomeronasal' amygdala in female mice selectively responds to volatile pheromones from males. Eur J Neurosci 29: 624–634.
Keshavarzi S, Sullivan RK, Ianno DJ, Sah P (2014). Functional properties and projections of neurons in the medial amygdala. J Neurosci 34: 8699–8715.
Kleinhans NM, Johnson LC, Richards T, Mahurin R, Greenson J, Dawson G et al (2009). Reduced neural habituation in the amygdala and social impairments in autism spectrum disorders. Am J Psychiatry 166: 467–475.
Kleinhans NM, Richards T, Sterling L, Stegbauer KC, Mahurin R, Johnson LC et al (2008). Abnormal functional connectivity in autism spectrum disorders during face processing. Brain 131: 1000–1012.
Kollack-Walker S, Newman SW (1997). Mating-induced expression of c-fos in the male Syrian hamster brain: role of experience, pheromones, and ejaculations. J Neurobiol 32: 481–501.
Lapiz MD, Fulford A, Muchimapura S, Mason R, Parker T, Marsden CA (2003). Influence of postweaning social isolation in the rat on brain development, conditioned behavior, and neurotransmission. Neurosci Behav Physiol 33: 13–29.
Lieberwirth C, Liu Y, Jia X, Wang Z (2012). Social isolation impairs adult neurogenesis in the limbic system and alters behaviors in female prairie voles. Horm Behav 62: 357–366.
Lukkes JL, Mokin MV, Scholl JL, Forster GL (2009). Adult rats exposed to early-life social isolation exhibit increased anxiety and conditioned fear behavior, and altered hormonal stress responses. Horm Behav 55: 248–256.
Makinodan M, Rosen KM, Ito S, Corfas G (2012). A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science 337: 1357–1360.
Maras PM, Petrulis A (2010). Lesions that functionally disconnect the anterior and posterodorsal sub-regions of the medial amygdala eliminate opposite-sex odor preference in male Syrian hamsters (Mesocricetus auratus. Neuroscience 165: 1052–1062.
Marsh AA, Finger EC, Mitchell DG, Reid ME, Sims C, Kosson DS et al (2008). Reduced amygdala response to fearful expressions in children and adolescents with callous-unemotional traits and disruptive behavior disorders. Am J Psychiatry 165: 712–720.
Martinez RC, Carvalho-Netto EF, Ribeiro-Barbosa ER, Baldo MV, Canteras NS (2011). Amygdalar roles during exposure to a live predator and to a predator-associated context. Neuroscience 172: 314–328.
McDonald AJ (1996). Glutamate and aspartate immunoreactive neurons of the rat basolateral amygdala: colocalization of excitatory amino acids and projections to the limbic circuit. J Comp Neurol 365: 367–379.
Meaney MJ, Stewart J (1981). Neonatal-androgens influence the social play of prepubescent rats. Horm Behav 15: 197–213.
Melo AI, Lovic V, Gonzalez A, Madden M, Sinopoli K, Fleming AS (2006). Maternal and littermate deprivation disrupts maternal behavior and social-learning of food preference in adulthood: tactile stimulation, nest odor, and social rearing prevent these effects. Dev Psychobiol 48: 209–219.
Meredith M, Westberry JM (2004). Distinctive responses in the medial amygdala to same-species and different-species pheromones. J Neurosci 24: 5719–5725.
Nataraj K, Le Roux N, Nahmani M, Lefort S, Turrigiano G (2010). Visual deprivation suppresses L5 pyramidal neuron excitability by preventing the induction of intrinsic plasticity. Neuron 68: 750–762.
National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals Guide for the Care and Use of Laboratory Animals. 8th edition. National Academies Press (US): Washington (DC); (2011).
Noack J, Murau R, Engelmann M (2015). Consequences of temporary inhibition of the medial amygdala on social recognition memory performance in mice. Front Neurosci 9: 152.
Paxinos CWG (2009) By George Paxinos—The Rat Brain in Stereotaxic Coordinates. 6th edn. Elsevier Science: Amsterdam.
Pellis SM, Field EF, Whishaw IQ (1999). The development of a sex-differentiated defensive motor pattern in rats: a possible role for juvenile experience. Dev Psychobiol 35: 156–164.
Petrulis A (2009). Neural mechanisms of individual and sexual recognition in Syrian hamsters (Mesocricetus auratus. Behav Brain Res 200: 260–267.
Phan KL, Fitzgerald DA, Nathan PJ, Tancer ME (2006). Association between amygdala hyperactivity to harsh faces and severity of social anxiety in generalized social phobia. Biol Psychiatry 59: 424–429.
Pinkham AE, Loughead J, Ruparel K, Overton E, Gur RE, Gur RC (2011). Abnormal modulation of amygdala activity in schizophrenia in response to direct- and averted-gaze threat-related facial expressions. Am J Psychiatry 168: 293–301.
Pitkanen A, Stefanacci L, Farb CR, Go GG, LeDoux JE, Amaral DG (1995). Intrinsic connections of the rat amygdaloid complex: projections originating in the lateral nucleus. J Comp Neurol 356: 288–310.
Potegal M, Einon D (1989). Aggressive behaviors in adult rats deprived of playfighting experience as juveniles. Dev Psychobiol 22: 159–172.
Richey JA, Rittenberg A, Hughes L, Damiano CR, Sabatino A, Miller S et al (2014). Common and distinct neural features of social and non-social reward processing in autism and social anxiety disorder. Soc Cogn Affect Neurosci 9: 367–377.
Rilling JK, Glenn AL, Jairam MR, Pagnoni G, Goldsmith DR, Elfenbein HA (2007). Neural correlates of social cooperation and non-cooperation as a function of psychopathy. Biol Psychiatry 61: 1260–1271.
Romeo RD, Sisk CL (2001). Pubertal and seasonal plasticity in the amygdala. Brain Res 889: 71–77.
Rudie JD, Shehzad Z, Hernandez LM, Colich NL, Bookheimer SY, Iacoboni M (2012). Reduced functional integration and segregation of distributed neural systems underlying social and emotional information processing in autism spectrum disorders. Cereb Cortex 22: 1025–1037.
Samuelsen CL, Meredith M (2009a). The vomeronasal organ is required for the male mouse medial amygdala response to chemical-communication signals, as assessed by immediate early gene expression. Neuroscience 164: 1468–1476.
Samuelsen CL, Meredith M (2009b). Categorization of biologically relevant chemical signals in the medial amygdala. Brain Res 1263: 33–42.
Sanchez MM, Aguado F, Sanchez-Toscano F, Saphier D (1995). Effects of prolonged social isolation on responses of neurons in the bed nucleus of the stria terminalis, preoptic area, and hypothalamic paraventricular nucleus to stimulation of the medial amygdala. Psychoneuroendocrinology 20: 525–541.
Schulz KM, Zehr JL, Salas-Ramirez KY, Sisk CL (2009). Testosterone programs adult social behavior before and during, but not after, adolescence. Endocrinology 150: 3690–3698.
Seffer D, Rippberger H, Schwarting RK, Wohr M (2015). Pro-social 50-kHz ultrasonic communication in rats: post-weaning but not post-adolescent social isolation leads to social impairments-phenotypic rescue by re-socialization. Front Behav Neurosci 9: 102.
Shoji H, Mizoguchi K (2011). Aging-related changes in the effects of social isolation on social behavior in rats. Physiol Behav 102: 58–62.
Smith GB, Heynen AJ, Bear MF (2009). Bidirectional synaptic mechanisms of ocular dominance plasticity in visual cortex. Philos Trans R Soc Lond Ser B 364: 357–367.
Stein MB, Goldin PR, Sareen J, Zorrilla LT, Brown GG (2002). Increased amygdala activation to angry and contemptuous faces in generalized social phobia. Arch Gen Psychiatry 59: 1027–1034.
Takahashi Y, Kiyokawa Y, Kodama Y, Arata S, Takeuchi Y, Mori Y (2013). Olfactory signals mediate social buffering of conditioned fear responses in male rats. Behav Brain Res 240: 46–51.
Toth M, Halasz J, Mikics E, Barsy B, Haller J (2008). Early social deprivation induces disturbed social communication and violent aggression in adulthood. Behav Neurosci 122: 849–854.
Toth M, Tulogdi A, Biro L, Soros P, Mikics E, Haller J (2012). The neural background of hyper-emotional aggression induced by post-weaning social isolation. Behav Brain Res 233: 120–129.
Tottenham N, Hertzig ME, Gillespie-Lynch K, Gilhooly T, Millner AJ, Casey BJ (2014). Elevated amygdala response to faces and gaze aversion in autism spectrum disorder. Soc Cogn Affect Neurosci 9: 106–117.
Unger EK, Burke KJJ, Yang CF, Bender KJ, Fuller PM, Shah NM (2015). Medial amygdalar aromatase neurons regulate aggression in both sexes. Cell Rep 10: 453–462.
van den Berg CL, Hol T, Van Ree JM, Spruijt BM, Everts H, Koolhaas JM (1999a). Play is indispensable for an adequate development of coping with social challenges in the rat. Dev Psychobiol 34: 129–138.
Van den Berg CL, Pijlman FT, Koning HA, Diergaarde L, Van Ree JM, Spruijt BM (1999b). Isolation changes the incentive value of sucrose and social behaviour in juvenile and adult rats. Behav Brain Res 106: 133–142.
Varty GB, Geyer MA (1998). Effects of isolation rearing on startle reactivity, habituation, and prepulse inhibition in male Lewis, Sprague–Dawley, and Fischer F344 rats. Behav Neurosci 112: 1450–1457.
von dem Hagen EA, Stoyanova RS, Baron-Cohen S, Calder AJ (2013). Reduced functional connectivity within and between ‘social’ resting state networks in autism spectrum conditions. Soc Cogn Affect Neurosci 8: 694–701.
Von Frijtag JC, Schot M, van den Bos R, Spruijt BM (2002). Individual housing during the play period results in changed responses to and consequences of a psychosocial stress situation in rats. Dev Psychobiol 41: 58–69.
Wall VL, Fischer EK, Bland ST (2012). Isolation rearing attenuates social interaction-induced expression of immediate early gene protein products in the medial prefrontal cortex of male and female rats. Physiol Behav 107: 440–450.
Wang AT, Dapretto M, Hariri AR, Sigman M, Bookheimer SY (2004). Neural correlates of facial affect processing in children and adolescents with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry 43: 481–490.
Ward IL, Reed J (1985). Prenatal stress and prepuberal social rearing conditions interact to determine sexual behavior in male rats. Behav Neurosci 99: 301–309.
Weng SJ, Carrasco M, Swartz JR, Wiggins JL, Kurapati N, Liberzon I et al (2011). Neural activation to emotional faces in adolescents with autism spectrum disorders. J Child Psychol Psychiatry 52: 296–305.
Williams LM, Das P, Harris AW, Liddell BB, Brammer MJ, Olivieri G et al (2004). Dysregulation of arousal and amygdala–prefrontal systems in paranoid schizophrenia. Am J Psychiatry 161: 480–489.
Wongwitdecha N, Marsden CA (1996). Social isolation increases aggressive behaviour and alters the effects of diazepam in the rat social interaction test. Behav Brain Res 75: 27–32.
Yusufishaq S, Rosenkranz JA (2013). Post-weaning social isolation impairs observational fear conditioning. Behav Brain Res 242: 142–149.
Zehr JL, Todd BJ, Schulz KM, McCarthy MM, Sisk CL (2006). Dendritic pruning of the medial amygdala during pubertal development of the male Syrian hamster. J Neurobiol 66: 578–590.
Acknowledgements
We thank Mallika Padival for the technical support. Grant support was provided by Simons Foundation (SFARI Award 283746 to JAR) and National Institutes of Health (R01MH084970 to JAR). The funding bodies had no role in the design of the study, collection, and analysis of data and decision to publish. The authors have no competing financial interests in relation to the work described.
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Adams, T., Rosenkranz, J. Social Isolation During Postweaning Development Causes Hypoactivity of Neurons in the Medial Nucleus of the Male Rat Amygdala. Neuropsychopharmacol 41, 1929–1940 (2016). https://doi.org/10.1038/npp.2015.364
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DOI: https://doi.org/10.1038/npp.2015.364
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