Psychosocial Stress, Environmental Enrichment, and Hippocampal Neurogenesis
A naturalistic model of chronic stress that mimics depressive conditions in humans is psychosocial stress, achieved in mice by creating a housing condition in which an aggressive dominant mouse and a subordinate mouse live together separated by a perforated barrier. The persistent conflict results in socially defeated subordinate mice that show behavioral signs of increased anxiety, helplessness, anhedonia, and inappropriate social interaction, assessed in validated behavioral tests. We showed that environmental enrichment — housing in large cages with tubes, toys, and a running wheel — following social defeat restores the normal behavior of the subordinate mice. We found that adult neurogenesis is required for the restorative effects. We also found that the environmental enrichment is protective when it is given prior to the psychosocial stress, and these effects are neurogenesis-dependent and require normal fluctuations in the stress hormone corticosterone. The photomicrograph shows newborn cells (BrdU-positive; yellow) in the germinal layer of the dentate gyrus.
- Lehmann, M.L., Brachman, R.A., Martinowich, K., Schloesser, R.J., and Herkenham, M. Glucocorticoids orchestrate divergent effects on mood through adult neurogenesis. J. Neurosci., 33: 2961-2972, 2013. Full Text/Abstract
- Lehmann, M. L., Geddes, C. E., Lee, J. L., and Herkenham, M. Urine scent marking (USM): A novel test for depressive-like behavior and a predictor of stress resiliency in mice. PLoS ONE, 8(7): e69822, 2013. Full Text/Abstract
- Lehmann, M.L. and Herkenham, M. Environmental enrichment confers stress resiliency to social defeat through an infralimbic cortex-dependent neuroanatomical pathway. J. Neuroscience, 31: 6159-6173, 2011. Full Text/Abstract
- Schloesser, R.J., Lehmann, M., Martinowich, K., Manji, H.K., Herkenham, M. Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress. Mol. Psychiatry, 15: 1152-1163, 2010. Full Text/Abstract
Neuroendocrine Components of the Stress Response
Our group previously studied the mechanisms of action of antidepressant drugs in animal models of depression. We documented changes in the hypothalamic-pituitary-adrenal (HPA) axis in response to acute or repeated immobilization in rats and mice. We showed that the corticotropin releasing hormone (CRH) and vasopressin systems of the hypothalamic paraventricular nucleus (PVN, seen in picture) and the locus coeruleus-norepinephrine system were involved in mediating both the effects of immobilization stress and compensatory actions of chronically administered antidepressant drugs. We showed similar kinds of changes in the HPA axis and in the hippocampus and bed nucleus of the stria terminalis, key way stations to the PVN, in animals given St. John's wort (Hypericum) chronically.
- Brady, L. S., Whitfield, H. J. Jr., Fox, R. J., Gold, P. W., and Herkenham, M. Long-term imipramine administration increases mineralocorticoid receptor mRNA in the hippocampus and decreases corticotropin-releasing hormone mRNA in the hypothalamus of rats. J. Clin. Invest., 87: 831-837, 1991.
- Butterweck, V. Winterhoff, H. and Herkenham, M. St. John's wort, hypericin, and imipramine: a comparative analysis of mRNA levels in brain areas involved in HPA axis control following short-term and long-term administration in normal and stressed rats. Mol. Psychiatry, 2001; 6: 547-564.
- Patchev, A., Fischer, D., Wolf, S., Herkenham, M., Gotz, F., Gehin, M., Chambon, P., Patchev, V., and Almeida, O. Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice. FASEB J., 21: 231-238, 2007
Parasynaptic Communication in the Nervous System
From paracrine to hormonal modes, parasynaptic actions of neuroactive molecules mediating intercellular information transfer are numerous and diverse. Anatomical evidence for parasynaptic communication includes nonsynaptic receptors, diffusion of neuroactive molecules from release sites, and nonsynaptic and even non-vesicular release. Functional actions in this mode may be inferred on the basis of mechanisms of drug effects, involvement of glia in interneuronal communication, cellular responses in culture, and hormone-like actions of neurotransmitters. It is concluded that parasynaptic mechanisms comprise the foundation for a large body of current neuroscience research.
- Herkenham M: Mismatches between neurotransmitter and receptor localizations in brain: observations and implications. Neuroscience, 1987; 23: 1-38.
- Herkenham M: Mismatches between neurotransmitter and receptor localizations: implications for endocrine functions in brain; in: Fuxe K, Agnati LF (eds): Volume Transmission in the Brain: Novel Mechanisms for Neural Transmission. New York, Raven Press, 1991, pp. 63-87.
- Herkenham M: Mismatches between receptor and transmitter localizations in the opiate system: implications for nonsynaptic opioid actions; in: Stumpf WE, Solomon HF (eds): Autoradiography and Correlative Imaging. New York, Raven Press, 1995, pp. 253-263.
- Proescholdt, M. G., Hutto, B., Brady, L. S., and Herkenham, M. Studies of cerebrospinal fluid flow and penetration into brain following lateral ventricle and cisterna magna injections of the tracer [14C]inulin in rat. Neuroscience, 2000, 95: 577-592.
- Herkenham, M. Extrasynaptic receptors and parasynaptic communication in the brain. Brain Res. Bull., 1999, 50: 351-352.
The Potential Role of the Fragile X Mental Retardation gene (fmr1) in Models of Adult Synaptic Plasticity
We sought to determine whether the fragile X mental retardation gene fmr1 is regulated in long-term potentiation (LTP) and electroconvulsive shock (ECS). In situ hybridization of fmr1 mRNA in hippocampus of rats given LTP in vivo showed no change in fmr1 mRNA levels relative to control. However, ECS induced a selective increase in fmr1 mRNA expression in the dentate gyrus granule cell layer at 6 h post-ECS. The ECS paradigm may unmask relevant activity-dependent regulatory mechanisms that modulate fmr gene transcription in vivo.
A Golgi-stained section of the dentate gyrus, showing the dentate granule cells, is shown in the picture.
- Bramham C, Southard T, Sarvey J, Herkenham M, Brady LS. Unilateral LTP triggers bilateral increases in hippocampal neurotrophin and trk receptor mRNA expression in behaving rats: evidence for interhemispheric communication. J Comp Neurol 1996; 368: 371-382.
- Valentine, G., Chakravarty, S., Sarvey,, J., Bramham, C., and Herkenham, M., Fragile X (fmr1) mRNA expression is differentially regulated in two adult models of activity-dependent gene expression. Mol. Brain Res., 2000: 75: 337-341.
Cannabinoid and Opioid Receptor Localization Studies
Techniques for localizing receptors recognized by neurotransmitters and psychoactive drugs were developed earlier in this laboratory. Brain maps of opioid (e.g. morphine) and cannabinoid (e.g. cannabis: marijuana) receptor distribution have been published. Opioid receptors are found in all parts of the brain, notably in sensory waystations and areas that control emotion (hypothalamus and amygdala), cognition (cerebral cortex), and pleasure (ventral forebrain). Cannabinoid receptors are localized in areas that control movement (basal ganglia, cerebellum), cognition (cerebral cortex), and attention and memory (hippocampus; see picture below).
Cannabinoid receptors are notably sparse in areas that control heart rate and respiration (medulla), explaining why there are not fatal overdoses of marijuana. Cannabinoid receptors are also located in areas that control emesis (nucleus of the solitary tract) and pain (see bottom), suggesting medical potential of marijuana. Receptors are not localized on ventral forebrain dopamine neurons that are implicated in abuse potential of psychoactive drugs, so effects of marijuana on "reward" systems are indirect.
- Herkenham, M. and Pert, C. B. In vitro autoradiography of opiate receptors in rat brain suggests loci of "opiatergic" pathways. Proc. Natl. Acad. Sci. U.S.A. 77: 5532-5536, 1980.
- Herkenham, M. and Pert C. B. Light microscopic localization of brain opiate receptors: a general autoradiographic method which preserves tissue quality. J. Neuroscience 2: 1129-1149, 1982.
- Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC: Cannabinoid receptor localization in brain. Proc. Natl. Acad. Sci. USA 87:1932-1936, 1990.
- Herkenham M: Localization of cannabinoid receptors in brain and periphery; in: Pertwee RG (ed): Cannabinoid Receptors. New York, Academic Press, 1995, pp. 145-166.
- Brady, L.S., Herkenham, M. Rothman, R.B., Partilla, J.S., Kšnig, M. Zimmer, A.M., and Zimmer, A. Regionally specific up-regulation of mu and delta opioid receptor binding in enkephalin knockout mice. Mol. Br. Res. 68: 193-197, 1999.
Cannabinoid Receptors as Therapeutic Targets: Pain Pathways.
Electrophysiological, neurochemical, and behavioral studies have shown that cannabinoids (marijuana-like drugs) suppress pain neurotransmission. To address the underlying mechanism, we have identified the locations of cannabinoid receptors in primary pain pathways using the techniques of in situ hybridization histochemistry and in vitro receptor binding/autoradiography. Central cannabinoid CB1 receptors are synthesized in cells of the dorsal root ganglia (see picture at left) and inserted on terminals in the spinal cord. In the dorsal root ganglia, identifying which cells carry pain information is achieved by labeling for substance P mRNA (marker of nociceptive cells).
In double-label experiments, we have determined that only a small fraction of substance P-positive cells also expresses CB1 mRNA. Furthermore, in the spinal cord where the nerve rootlets terminate in the dorsal horn, only a portion of cannabinoid receptors is found presynaptically on central terminals of primary afferents, and the remainder is located on processes of the spinal cord itself. We think that these results have implications for how cannabinoids may work in chronic pain states. A differential anatomical basis underlying cannabinoid and mu opioid modulation of primary afferent transmission is supported.
Whereas mu opioid receptors in spinal cord are associated predominantly with thin-diameter primary afferents, cannabinoid receptors are localized to both thin and coarse diameter fibers. These differences may provide a basis for the possibility that cannabinoids may relieve pain when traditional opiate drugs fail.
- Hohmann, A. G., Briley, E. M., and Herkenham, M. Pre- and post-synaptic distribution of cannabinoid and mu opioid receptors in rat spinal cord. Brain Research, 822: 17-25, 1998.
- Hohmann, A.G. and Herkenham, M. Regulation of cannabinoid and mu opioid receptors in rat lumbar spinal cord following neonatal capsaicin treatment. Neurosci. Lett., 252: 13-16, 1998.
- Hohmann, A. G. and Herkenham, M. Localization of cannabinoid receptor CB1 mRNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study. Neuroscience, 90: 923-931, 1999.
- Hohmann, A. G. and Herkenham, M. Cannabinoid receptors undergo axonal flow in sensory nerves. Neurosicence, 92: 1171-1175, 1999.