Advances in Neuroimmune Biology 4 (2013) 13–33 13 DOI 10.3233/NIB-130054 IOS Press Neuroanatomy of Stress Responses Takashi Ueyama∗ Department of Anatomy and Cell Biology, Wakayama Medical University Graduate School of Medicine, Kimiidera, Wakayama, Japan Abstract. The autonomic nervous system, especially the sympathetic nervous system, regulates immune responses, while cytokines produced in the immune system also affect neuronal activities. Stress-induced expression of immediate early genes, such as c-Fos in the brain, and the viral transneuronal labeling using pseudorabies virus make it possible to analyze the neuro- circuitry of the stress-related central autonomic nervous system. Limbic systems (amygdala, lateral septum, infralimbic, insular, ventromedial temporal cortical regions), and several hypothalamic and brainstem nuclei have been identified as the central sites that regulate stress-induced sympathetic nervous activation. This review focuses on the involvement of the amygdala in the regulation of stress-induced sympathetic nervous responses. All amygdaloid subnuclei receive psychological information from other limbic regions, while the lateral and central subnuclei receive sensory and immune information from parabrachial nucleus and medical geniculate nucleus. Output to the hypothalamus mainly originates from the medial amygdala, while output to the bed nucleus of the stria terminalis originates from the central amygdala and the medial amygdala. Sex steroids such as estrogen and androgen can modulate the sympathetic nervous activity since their receptors are expressed in the medial amygdala. Keywords: Amygdala, central autonomic nervous system, immediate early genes, projection, sex steroids, viral trans-neuronal labeling ABBREVIATIONS AI agranular insular cortex AP area postrema APir amygdalopiriform transition area A5 A5 noradrenaline cells Arc arcuate hypothalamic nucleus A7 A7 noradrenaline cells BAOT bed nucleus of the accessory olfactory tract AA anterior amygdaloid area BL basolateral amygdaloid nucleus Acb accumbens nucleus BLA basolateral amygdaloid nucleus, anterior AcbC accumbens nucleus, core part AcbSh accumbens nucleus, shell BLP basolateral amygdaloid nucleus, posterior ACo anterior cortical amygdaloid nucleus part AH anterior hypothalamic area BLV basolateral amygdaloid nucleus, ventral AHi amygdalohippocampal area part AHiAL amygdalohippocampal area, anterolateral BM basomedial amygdaloid nucleus part BMA basomedial amygdaloid nucleus, anterior AHiPM amygdalohippocampal area, posteromedial part part BMP basomedial amygdaloid nucleus, posterior part ∗ Correspondence to: Takashi Ueyama, M.D., Ph.D., Department BST bed nucleus of the stria terminalis of Anatomy and Cell Biology, Wakayama Medical University Grad- BSTIA bed nucleus of the stria terminalis, uate School of Medicine, 811-1, Kimiidera, Wakayama, 641-8509, Japan. Tel./Fax: +81 73 441 0616; E-mail: tueyama@wakayama- intraamygdaloid division med.ac.jp. CA1 field CA1 of the hippocampus ISSN 1878-948X/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License. 14 T. Ueyama / Neuroanatomy of Stress Responses CA2 field CA2 of the hippocampus LPMR lateral posterior thalamic nucleus, CA3 field CA3 of the hippocampus mediorostral part CeA central amygdaloid nucleus LPO lateral preoptic area CeC central amygdaloid nucleus, capsular part LS lateral septal nucleus CeL central amygdaloid nucleus, lateral division LSD lateral septal nucleus, dorsal part CeM central amygdaloid nucleus, medial LSI lateral septal nucleus, intermediate part division LSV lateral septal nucleus, ventral part Cgl cingulate cortex, area 1 M1 primary motor cortex CM central medial thalamic nucleus M2 secondary motor cortex CPu caudate putamen (striatum) MCPO magnocellular preoptic nucleus CoA cortical amygdaloid nucleus MD mediodorsal thalamic nucleus CxA cortex-amygdala transition zone MeA medial amygdaloid nucleus DEn dorsal endopiriform nucleus MeAD medial amygdaloid nucleus, anterodorsal DLL dorsal nucleus of the lateral lemniscus part DLPAG dorsolateral periaqueductal gray MeAV medial amygdaloid nucleus, anteroventral DMH dorsomedial hypothalamic nucleus part DMPAG dorsomedial periaqueductal gray MePD medial amygdaloid nucleus, posterodorsal DP dorsal peduncular cortex part DpMe deep mesencephalic nucleus MePV medial amygdaloid nucleus, posteroventral DR dorsal raphe nucleus part DRC dorsal raphe nucleus, caudal part MG medial geniculate nucleus DRD dorsal raphe nucleus, dorsal part MGD medial geniculate nucleus, dorsal part DTgP dorsal tegmental nucleus, pericentral part MGM medial geniculate nucleus, medial part Ect ectorhinal cortex MHb medial habenular nucleus Eth ethmoid thalamic nucleus MM medial mammillary nucleus, medial part EW Edinger-Westphal nucleus MO medial orbital cortex GiV gigantocellular reticular nucleus, ventral MPA medial preoptic area part MPB medial parabrachial nucleus HDB nucleus of the horizontal limb of the MPO medial preoptic nucleus diagonal band MS medial septal nucleus IAM interanteromedial thalamic nucleus NTS nucleus of the solitary tract IL infralimbic cortex opt optic tract IM intercalated amygdaloid nucleus, PaAP parventricular hypothalamic nucleus, main part anterior parvicellular part IPAC interstitial nucleus of the posterior limb of PB parabrachial nucleus the anterior commissure Pe periventricular hypothalamic nucleus LaA lateral amygdaloid nucleus PeF perifornical nucleus LaDL lateral amygdaloid nucleus, dorsolateral PF parafascicular thalamic nucleus part PH posterior hypothalamic area LaVL lateral amygdaloid nucleus, ventrolateral PIL posterior intralaminar thalamic nucleus part Pir piriform cortex LaVM lateral amygdaloid nucleus, ventromedial PLCo posterolateral cortical amygdaloid part nucleus LC locus coeruleus PMCo posteromedial cortical amygdaloid nucleus LDTg laterodorsal tegmental nucleus PMD premammillary nucleus, dorsal part LEnt lateral entorhinal cortex PMV premammillary nucleus, ventral part LH lateral hypothalamic area PP peripeduncular nucleus LO lateral orbital cortex PRh perirhinal cortex LPAG lateral periaqueductal gray PrL prelimbic cortex LPB lateral parabrachial nucleus PSTh parasubthalamic nucleus LPGi lateral paragigantocellular nucleus PT paratenial thalamic nucleus T. Ueyama / Neuroanatomy of Stress Responses 15 PV paraventricular thalamic nucleus ous changes in cellular signaling pathways, resulting PVA paraventricular thalamic nucleus, anterior in alterations of gene expression for cytokines and part antibodies. Recently, the involvement of the parasym- PVH paraventricular hypothalamic nucleus pathetic nervous system on immune regulation has PVP paraventricular thalamic nucleus, posterior been also reported. For example, stimulation of the part vagus nerve attenuates cytokine production, thereby RCh retrochiasmatic area improving survival in experimental sepsis, hemor- REth retroethmoid nucleus rhagic shock, ischemia-reperfusion injury, and other RMg raphe magnus nucleus conditions of cytokine excess [2]. Proinflammatory RPa raphe pallidus nucleus cytokines such as interleukin-1␤ (IL-1␤), tumor necro- RVL rostroventrolateral reticular nucleus sis factor-␣ (TNF-␣) and interleukin-6 (IL-6) and S subiculum other chemical mediators produced in the immune S1 primary somatosensory cortex systems also affect neuronal activities. Cytokines and S2 secondary somatosensory cortex their receptors are expressed in the nervous sys- SCN suprachiasmatic nucleus tems, and may be attributed to invading immune, or SI substantia innominata resident cells [3, 4]. Neuronal immune-modulations SO supraoptic nucleus are conducted within the central nervous system SPFPC subparafascicular thalamic nucleus, (CNS). For instance, neural activity of the amyg- parvicellular part dala and insular cortex as measured by implanted SubB subbrachial nucleus deep-brain electrodes is not only specific for the SuM supramammillary nucleus type of immune challenge (T-cell-independent antigen TeA temporal association cortex lipopolysaccharide versus the T-cell-dependent anti- Tu olfactory tubercle gen staphylococcal enterotoxin B), but also sensitive to VC ventral cochlear nucleus different immune states (naive versus desensitization) VDB nucleus of the ventral limb of the diagonal [5]. band The first purpose of this review is to introduce recent VEn ventral endopiriform nucleus advances in central autonomic nervous system that reg- VLPAG ventrolateral periaqueductal gray ulates the peripheral sympathetic nervous system by a VMH ventromedial hypothalamic nucleus comparison of the data from different kinds of neu- VP ventral pallidum roanatomical labeling techniques. The second purpose VPL ventral posterolateral thalamic nucleus of this review is to reinvestigate and summarize the VTM ventral tuberomammilary nucleus exra- and intra-amygdala projections into major subnu- ZI zona incerta clei of the amygdala, a key-relay and integrative region of the central autonomic nervous system, and projec- tions from the medical amygdaloid nucleus and from the central amydgaloid nucleus. INTRODUCTION Bidirectional interactions between the autonomic nervous system (sympathetic nervous system and CENTRAL AUTONOMIC NERVOUS parasympathetic nervous system) and the immune sys- SYSTEM tem have been studied extensively. The immune system is regulated mainly by the sympathetic nervous system, The peripheral autonomic nervous system