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Invited Review the Distribution of Cholinergic Neurons in the Human

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Invited Review the Distribution of Cholinergic Neurons in the Human Histol Histopalhol (2000) 15: 825-834 Histology and 001 : 10.14670/HH-15.825 Histopathology http://www.hh.um.es Cellular and Molecular Biology Invited Review The distribution of cholinergic neurons in the human central nervous system V. Oda and I. Nakanishi First Department of Pathology, Faculty of Medicine, Kanazawa University, Japan Summary. Choline acetyltransferase (ChAT), the arousal, sleep and movement (Butcher and Woolf, 1986; enzyme responsible for the biosynthesis of Woolf, 1991). Selective loss of cholinergic neurons in acetylcholine, is presently the most specific marker for the basal forebrain has been observed in Alzheimer's identifying cholinergic neurons in the central and disease (Perry et ai., 1978; Whitehouse et ai., 1981). peripheral nervous systems. The present article reviews Amyotrophic lateral sclerosis and Huntington's disease immunohistochemical and in situ hybridization studies a re other neurodegenerative di sorders in which on the distribution of neurons ex pressing ChAT in the cholinergic neurons are affected. Choline acetyl­ human central nervous system. Neurons with both transferase (ChAT, acetyl CoA:choline O-acetyl­ immunoreactivity and in situ hybridization signals of transferase, EC 2.3.1.6), the enzyme responsible for the ChAT are observed in the basal forebrain (diagonal band biosynthesis of acetylcholine, is presently the most of Broca and nucleus basalis of Meynert), striatum specific indicator for monitoring the functional state of (caudate nucleus, putamen and nucleus accumbens), cholinergic neurons in the central and peripheral nervous cerebral cortex, mesopontine tegmental nuclei systems. This enzyme is also a useful specific marker for (pedunculopontine tegmental nucleus , laterodorsal identifying cholinergic neurons in the nervous system. tegmental nucleus and parabigeminal nucleus), cranial During the past 20 years, several polyclonal and motor nuclei and spinal motor neurons. The cerebral monoclonal anti-ChAT antibodies have been developed cortex displays regional and laminal differences in the and applied in anatomical analyses of the central distribution of neurons with ChAT. The medial seotal cholinergic organization in mammalian species. More nucleus and medial habenular nucleus contain recently, following the successful cDNA cloning for immunoreactive neurons for ChAT, which are devoid of ChAT, an in situ hybridization technique has been ChAT mRNA signals. This is probably because there is a induced to detect ChAT mRNA in neurons for small number of cholinergic neurons with a low level of identifying authentic cholinergic neurons. The present ChAT gene expression in these nuclei of human. article reviews immunohistochemical and in situ Possible connections and speculated functions of these hybridization studies on the distribution of neurons neurons are briefly summarized. expressing ChAT in the human central nervous system. Key words: Choline acetyltransferase, Central nervous Localization of neuronal cell body with ChAT system, Human, Immunohi stochemistry, In situ immunoreactivity and in situ hybridization signals hybridization Based on immunohistochemical studies of monkey and rodent brains , Mesulam (1988) proposed a Introduction nomenclature to describe ChAT-immonoreactive neurons which are aggregated in eight major groups: Chl-Ch8. Neurons that synthesize and release acetylcholine for Chi designates the ChAT-containing neurons associated neurotransmission are referred to as cholinergic neurons. with the medial septal nucleus , Ch2 is associated with Cholinergic neurons in the mammalian central nervous the vertical nucleus of the diagonal band of Broca, Ch3 system are thought to play an important role in with the horizontal limb nucleus of the diagonal band of fundamental brain functions, such as learning, memory, Broca, Ch4 with the nucleus basalis of the substantia innominata, ChS with the pedunculopontine nucleus of Offprint requests to: Dr. Yoshio Oda, MD , Associate professor, First the rostal brain stem, Ch6 with the laterodorsal Department of Pathology, Faculty of Medicine, Kanazawa University, tegmental nucleus of the rostal brain stem, Ch7 with the 13-1 Takara-machi, Kanazawa, Ishikawa 920·8640, Japan, e·mail : medial habenula, and Ch8 is associated with those yoda@med ,kanazawa-u ,ac.jp neurons in the parabigeminal nucleus. In addition, the 826 Human central cholinergic neuron striate nucleus, cerebral cortex, some cranial nerve detected in the medial septal nucleus (ChI), nucleus of nuclei and the spinal cord gray matter also contain the diagonal band of Broca (Ch2 and Ch3), the basal ChAT-immunoreactive neurons. This cl assification is nucleus of Meynert (Ch4), the caudate nucleus, the applicable in describing the human central cholinergic putamen, the nucleus accumbens (the ventral striatum), system. In human, ChAT-immunoreactive neurons are the pedunculoponline tegme ntal nucleus (Ch5), the , . Coronal section though Coronal section through the the cerebral nuclei thalamus '. Fig. 1. Schematic representation of the distribution of chOlinerg ic neurons in the human central nervous system, Closed circles indicate Transverse section Transverse section Transverse section neurons with both ChAT at the level at the level of immunoreactivity and of the midbrain of the upper portion the lumbar cord mRNA; open circles indicate those with ChAT of the pons immunoreactivity only, 827 Human central cholinergic neuron laterodorsal tegmental nucleus (Ch6), the medial low level of ChAT gene expression in this nucleus habenular nucleus (Ch7), the parabigeminal nucleus (Kasashima et aI., 1998). (Ch8), some distinct areas of the cerebral cortex, some cranial nerve nuclei, and the anterior gray horn of the 2. Diagonal band of Broca (Ch2 and Ch3) spinal cord. Furthermore, nucleus subputaminalis (Ayala), which has long been disregarded in The diagonal band of Broca is located from the morphological studies, contains ChAT-immunoreactive ventromedial portion of the lateral septum (vertical limb neurons (Simic et aI., 1999). Table 1 summarizes the of the diagonal band, Ch2) to the ventrorostromedial results of immunohistochemical and in situ hybridization portion of the subcommissural region (horizontal limb of studies and Figure 1 shows a schematic representation of the diagonal band, Ch3) below Ch4. The boundary the distribution of neurons containing ChAT in the between the medial septal nucleus and the vertical limb human central nervous system. of the diagonal band (Ch2) is not clearly defined, an area in which neurons are rather sparsely distributed. I. Magnocel/ular nuclei of the basal forebrain Sometimes, the two structures are categorized together as Ch1-2. The shape of Ch3 is ill-defined, where neurons Magnocellular nuclei of the basal forebrain are are scattered randomly. ChAT-immunoreactive neurons composed of the medial septal nucleus, the nucleus of in the diagonal band are large, polygonal (particularly in the diagonal band and the basal nucleus of Meynert. the vertical) or fusiform (particularly in the horizontal These structures are tightly connected to each other limb). An in situ hybridization study revealed that large (Ulfig, 1989). In addition, a recent histochemical and neurons in this area contain hybridization signals for immunohistochemical study pointed out that the nucleus ChAT (Kasashima et aI., 1998). subputaminalis is also a component of the magnocellular complex (Simic et aI., 1999). 3. Nucleus basalis of Meynert (Ch4) 1. Medial septal nucleus (ChI) The nucleus basalis of Meynert is a continuous plate of neurons, which occupies the sub lenticular region The medial septal nucleus located in the septum between the sagittal levels of the olfactory tubercle and verum forms the anteromost portion of the basal the lateral geniculate nucleus. Based on a cyto­ magnocellular complex. Large, ovoid neurons with architectural study of monkey brain (Mesulam et aI., vertical orientation are immunopositive for ChAT. The 1983), Mesulam and Geula (1988) stated that the human immunoreactivity of the neurons is relatively weak Ch4 complex can also be subdivided into six sectors that compared with that of neurons in other magnocellular occupy its anteromedial (Ch4am), anterolateral (Ch4al), complex areas such as the nucleus basalis of Meynert. In anterointermediate (Ch4ai), intermediodorsal (Ch4id), situ hybridization failed to detect positive signals for intermedioventral (Ch4iv) and posterior (Ch4p) regions. ChAT mRNA in the neurons. This is probably because Some other researchers used this classification in there is a small number of cholinergic neurons with a morphological studies of the human basal forebrain A B Fig. 2. Immunohistochemistry (A) and in situ mRNA hybridization (8. dark field) studies of ChAT in the nucleus basalis of Meynert. Most of the large neurons are labeled. x 87.5 828 Human central cholinergic neuron Table 1. Regional distribution of neurons with choline acetyltransferase immunoreactivity and mRNA in the human central nervous system IMMUNOHISTOCHEMISTRY IN SITU HYBRIDIZATION Basal forebrain Medial septal nucleus + Nucleus of diagonal band of Broca + + Nucleus basalis of Meynert + + Nucleus subputaminalis + + Amygdala Basal ganglia Caudate nucleus + + Putamen + + Globus pallidus Thalamus Epithalamus Medial habenular nucleus + Lateral habenular nucleus Hippocampus Enthorhinal cortex + + Neocortex Brodmann's areas 1, 2, 3 (somatosensory) 4 (somatomotor) + + 6, 8, 9 (premotor) + 17 (fi rst visual) 18 (secondary visual) + 20,21 22 (secondary
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