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Ultrastructural analysis of sex differences in nucleus accumbens synaptic connectivity

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Abstract

Despite robust sex differences in behavioral responses to drugs of abuse, relatively little is known about structural sex differences in synaptic connectivity of reward circuits such as in the nucleus accumbens (NAc). Previously, we showed that distal dendritic spine density on medium spiny neurons in the NAc is higher in females than males, suggesting that sex differences in NAc excitatory synapses could play a role in differential behavioral responses to drugs. In the current study, we used electron microscopy and stereological counting methods to evaluate dendritic spine and shaft synapses, as well as tyrosine hydroxylase-immunoreactive (TH-IR) profiles, in the NAc core of male and female rats. We found an unanticipated rostro-caudal gradient in spine synapse density in females but not males, resulting in a sex difference favoring females in the caudal NAc core. The volume of the NAc was not different between males and females. We also found that the percentage of spines with large spine heads was greater in females in the rostral core. The density of shaft synapses was low compared to spine synapses, and sex differences were minor. The density of TH-IR profiles was not different between males and females, but females had a higher proportion of spines with large heads near TH suggesting a potential sex difference in dopaminergic modulation of large spine synapses. These findings underscore the importance of including both males and females in studies of reward circuitry, and of considering variation along the rostro-caudal axis of the NAc in future studies.

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References

  • Alcantara AA, Lim HY, Floyd CE, Garces J, Mendenhall JM, Lyons CL, Berlanga ML (2011) Cocaine- and morphine-induced synaptic plasticity in the nucleus accumbens. Synapse 65:309–320

    Article  PubMed  CAS  Google Scholar 

  • Becker JB (1990) Estrogen rapidly potentiates amphetamine-induced striatal dopamine release and rotational behavior during microdialysis. Neurosci Lett 118:169–171

    Article  PubMed  CAS  Google Scholar 

  • Becker JB (1999) Gender differences in dopaminergic function in striatum and nucleus accumbens. Pharmacol Biochem Behav 64:803–812

    Article  PubMed  CAS  Google Scholar 

  • Becker JB, Cha JH (1989) Estrous cycle-dependent variation in amphetamine-induced behaviors and striatal dopamine release assessed with microdialysis. Behav Brain Res 35:117–125

    Article  PubMed  CAS  Google Scholar 

  • Becker JB, Hu M (2008) Sex differences in drug abuse. Front Neuroendocrinol 29:36–47

    Article  PubMed  CAS  Google Scholar 

  • Berendse HW, Galis-de Graaf Y, Groenewegen HJ (1992) Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat. J Comp Neurol 316:314–347

    Article  PubMed  CAS  Google Scholar 

  • Bouyer JJ, Joh TH, Pickel VM (1984) Ultrastructural localization of tyrosine hydroxylase in rat nucleus accumbens. J Comp Neurol 227:92–103

    Article  PubMed  CAS  Google Scholar 

  • Brog JS, Salyapongse A, Deutch AY, Zahm DS (1993) The patterns of afferent innervation of the core and shell in the “accumbens” part of the rat ventral striatum: immunohistochemical detection of retrogradely transported fluoro-gold. J Comp Neurol 338:255–278

    Article  PubMed  CAS  Google Scholar 

  • Carroll ME, Anker JJ (2010) Sex differences and ovarian hormones in animal models of drug dependence. Horm Behav 58:44–56

    Article  PubMed  CAS  Google Scholar 

  • David HN, Sissaoui K, Abraini JH (2004) Modulation of the locomotor responses induced by D1-like and D2-like dopamine receptor agonists and d-amphetamine by NMDA and non-NMDA glutamate receptor agonists and antagonists in the core of the rat nucleus accumbens. Neuropharmacology 46:179–191

    Article  PubMed  CAS  Google Scholar 

  • Dobi A, Seabold GK, Christensen CH, Bock R, Alvarez VA (2011) Cocaine-induced plasticity in the nucleus accumbens is cell specific and develops without prolonged withdrawal. J Neurosci 31:1895–1904

    Article  PubMed  CAS  Google Scholar 

  • Fiala JC, Harris KM (2001) Cylindrical diameters method for calibrating section thickness in serial electron microscopy. J Microsc 202:468–472

    Article  PubMed  CAS  Google Scholar 

  • Forlano PM, Woolley CS (2010) Quantitative analysis of pre- and postsynaptic sex differences in the nucleus accumbens. J Comp Neurol 518:1330–1348

    Article  PubMed  CAS  Google Scholar 

  • Gill KM, Grace AA (2011) Heterogeneous processing of amygdala and hippocampal inputs in the rostral and caudal subregions of the nucleus accumbens. Int J Neuropsychopharmacol 1–14. doi:10.1017/S1461145710001586

  • Hart SA, Snyder MA, Smejkalova T, Woolley CS (2007) Estrogen mobilizes a subset of estrogen receptor-alpha-immunoreactive vesicles in inhibitory presynaptic boutons in hippocampal CA1. J Neurosci 27:2102–2111

    Article  PubMed  CAS  Google Scholar 

  • Heidbreder C, Feldon J (1998) Amphetamine-induced neurochemical and locomotor responses are expressed differentially across the anteroposterior axis of the core and shell subterritories of the nucleus accumbens. Synapse 29:310–322

    Article  PubMed  CAS  Google Scholar 

  • Heidbreder CA, Hedou G, Feldon J (1999) Behavioral neurochemistry reveals a new functional dichotomy in the shell subregion of the nucleus accumbens. Prog Neuropsychopharmacol Biol Psychiatry 23:99–132

    Article  PubMed  CAS  Google Scholar 

  • Hu M, Becker JB (2003) Effects of sex and estrogen on behavioral sensitization to cocaine in rats. J Neurosci 23:693–699

    PubMed  CAS  Google Scholar 

  • Kauer JA, Malenka RC (2007) Synaptic plasticity and addiction. Nat Rev Neurosci 8:844–858

    Article  PubMed  CAS  Google Scholar 

  • Keuker JI, Vollmann-Honsdorf GK, Fuchs E (2001) How to use the optical fractionator: an example based on the estimation of neurons in the hippocampal CA1 and CA3 regions of tree shrews. Brain Res Brain Res Protoc 7:211–221

    Article  PubMed  CAS  Google Scholar 

  • Koob GF, Volkow ND (2010) Neurocircuitry of addiction. Neuropsychopharmacology 35:217–238

    Article  PubMed  Google Scholar 

  • Kourrich S, Thomas MJ (2009) Similar neurons, opposite adaptations: psychostimulant experience differentially alters firing properties in accumbens core versus shell. J Neurosci 29:12275–12283

    Article  PubMed  CAS  Google Scholar 

  • Lee KW, Kim Y, Kim AM, Helmin K, Nairn AC, Greengard P (2006) Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens. Proc Natl Acad Sci USA 103:3399–3404

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Kolb B, Robinson TE (2003) The location of persistent amphetamine-induced changes in the density of dendritic spines on medium spiny neurons in the nucleus accumbens and caudate-putamen. Neuropsychopharmacology 28:1082–1085

    Article  PubMed  CAS  Google Scholar 

  • Magee JC, Cook EP (2000) Somatic EPSP amplitude is independent of synapse location in hippocampal pyramidal neurons. Nat Neurosci 3:895–903

    Article  PubMed  CAS  Google Scholar 

  • Martin M, Chen BT, Hopf FW, Bowers MS, Bonci A (2006) Cocaine self-administration selectively abolishes LTD in the core of the nucleus accumbens. Nat Neurosci 9:868–869

    Article  PubMed  CAS  Google Scholar 

  • Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H (2004) Structural basis of long-term potentiation in single dendritic spines. Nature 429:761–766

    Article  PubMed  CAS  Google Scholar 

  • McAvoy T, Zhou MM, Greengard P, Nairn AC (2009) Phosphorylation of Rap1GAP, a striatally enriched protein, by protein kinase A controls Rap1 activity and dendritic spine morphology. Proc Natl Acad Sci USA 106:3531–3536

    Article  PubMed  CAS  Google Scholar 

  • Meredith GE, Farrell T, Kellaghan P, Tan Y, Zahm DS, Totterdell S (1999) Immunocytochemical characterization of catecholaminergic neurons in the rat striatum following dopamine-depleting lesions. Eur J Neurosci 11:3585–3596

    Article  PubMed  CAS  Google Scholar 

  • Mouton PR, Gokhale AM, Ward NL, West MJ (2002) Stereological length estimation using spherical probes. J Microsc 206:54–64

    Article  PubMed  CAS  Google Scholar 

  • Nicholson DA, Trana R, Katz Y, Kath WL, Spruston N, Geinisman Y (2006) Distance-dependent differences in synapse number and AMPA receptor expression in hippocampal CA1 pyramidal neurons. Neuron 50:431–442

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Elsevier Academic Press, Boston

    Google Scholar 

  • Reynolds SM, Berridge KC (2003) Glutamate motivational ensembles in nucleus accumbens: rostrocaudal shell gradients of fear and feeding. Eur J Neurosci 17:2187–2200

    Article  PubMed  Google Scholar 

  • Robinson TE, Kolb B (1999a) Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine. Eur J Neurosci 11:1598–1604

    Article  PubMed  CAS  Google Scholar 

  • Robinson TE, Kolb B (1999b) Morphine alters the structure of neurons in the nucleus accumbens and neocortex of rats. Synapse 33:160–162

    Article  PubMed  CAS  Google Scholar 

  • Russo SJ, Dietz DM, Dumitriu D, Morrison JH, Malenka RC, Nestler EJ (2010) The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci 33:267–276

    Article  PubMed  CAS  Google Scholar 

  • SAMHSA (2010) Results from the 2009 National Survey on Drug Use and Health: volume I. Summary of National Findings (Office of Applied Studies, NSDUH Series H-38A, HHS Publication No. SMA 10-4856Findings). Rockville

  • Sato SM, Wissman AM, McCollum AF, Woolley CS (2011) Quantitative mapping of cocaine-induced deltafosb expression in the striatum of male and female rats. PLoS One 6:e21783

    Article  PubMed  CAS  Google Scholar 

  • Smith MS, Freeman ME, Neill JD (1975) The control of progesterone secretion during the estrous cycle and early pseudopregnancy in the rat: prolactin, gonadotropin and steroid levels associated with rescue of the corpus luteum of pseudopregnancy. Endocrinology 96:219–226

    Article  PubMed  CAS  Google Scholar 

  • Smith GT, Brenowitz EA, Wingfield JC (1997) Roles of photoperiod and testosterone in seasonal plasticity of the avian song control system. J Neurobiol 32:426–442

    Article  PubMed  CAS  Google Scholar 

  • Smith SL, Judy JW, Otis TS (2004) An ultra small array of electrodes for stimulating multiple inputs into a single neuron. J Neurosci Methods 133:109–114

    Article  PubMed  Google Scholar 

  • Todtenkopf MS, Stellar JR (2000) Assessment of tyrosine hydroxylase immunoreactive innervation in five subregions of the nucleus accumbens shell in rats treated with repeated cocaine. Synapse 38:261–270

    Article  PubMed  CAS  Google Scholar 

  • Totterdell S, Smith AD (1989) Convergence of hippocampal and dopaminergic input onto identified neurons in the nucleus accumbens of the rat. J Chem Neuroanat 2:285–298

    PubMed  CAS  Google Scholar 

  • Usuda I, Tanaka K, Chiba T (1998) Efferent projections of the nucleus accumbens in the rat with special reference to subdivision of the nucleus: biotinylated dextran amine study. Brain Res 797:73–93

    Article  PubMed  CAS  Google Scholar 

  • van Haaren F, Meyer ME (1991) Sex differences in locomotor activity after acute and chronic cocaine administration. Pharmacol Biochem Behav 39:923–927

    Article  PubMed  Google Scholar 

  • Wissman AM, McCollum AF, Huang GZ, Nikrodhanond AA, Woolley CS (2011) Sex differences and effects of cocaine on excitatory synapses in the nucleus accumbens. Neuropharmacology 61:217–227

    Article  PubMed  CAS  Google Scholar 

  • Wright CI, Groenewegen HJ (1995) Patterns of convergence and segregation in the medial nucleus accumbens of the rat: relationships of prefrontal cortical, midline thalamic, and basal amygdaloid afferents. J Comp Neurol 361:383–403

    Article  PubMed  CAS  Google Scholar 

  • Xie Z, Huganir RL, Penzes P (2005) Activity-dependent dendritic spine structural plasticity is regulated by small GTPase Rap1 and its target AF-6. Neuron 48:605–618

    Article  PubMed  CAS  Google Scholar 

  • Zahm DS (2000) An integrative neuroanatomical perspective on some subcortical substrates of adaptive responding with emphasis on the nucleus accumbens. Neurosci Biobehav Rev 24:85–105

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by National Institutes of Health R01 DA020492 to CSW. The authors thank Dr. Paul Forlano for assistance with tissue preparation.

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The authors declare that they have no conflict of interest.

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Correspondence to Catherine S. Woolley.

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A. M. Wissman and R. M. May contributed equally to this manuscript.

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Wissman, A.M., May, R.M. & Woolley, C.S. Ultrastructural analysis of sex differences in nucleus accumbens synaptic connectivity. Brain Struct Funct 217, 181–190 (2012). https://doi.org/10.1007/s00429-011-0353-6

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  • DOI: https://doi.org/10.1007/s00429-011-0353-6

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