George F. Alheid

Cholecystokinin innervation of the ventral striatum: A morphological and radioimmunological study

Immunocytochemistry, radioimmunological assay after surgical cuts, anterograde degeneration and retrograde tracing of fluorescent dyes were used in order to elucidate the cholecystokinin-containing afferents to the ventral striatum (nucleus accumbens, olfactory tubercle and ventral part of the caudate-putamen). In agreement with the report by Hökfelt et al., midbrain cholecystokinin-containing cells supply the posteromedial parts of the nucleus accumbens and olfactory tubercle, as well as the subcommissural part of caudate-putamen. Brainstem cholecystokinin afferents also reach more rostral parts of the ventral striatum including the rostrolateral olfactory tubercle. The ascending cholecystokinin axons enter the medial forebrain bundle at the meso-diencephalic border and maintain a rough medial to lateral topography at the caudal diencephalon. A second major cholecystokinin pathway, with possible origin in the piriform and medial prefrontal cortices and/or the amygdala, projects to the subcommissural caudate-putamen, the olfactory tubercle, the lateral part of the nucleus accumbens and the dorsal part of the bed nucleus of stria terminalis. Finally, the rostral part of the dorsal caudate-putamen receives a substantial cholecystokinin innervation from the basolateral amygdala and possibly from the neocortex. According to radioimmunological data, the descending telencephalic cholecystokinin system accounts for about 60% of all cholecystokinin in the rostral forebrain. The combined use of morphological and biochemical methods provided evidence for a partially overlapping distribution and possible interaction between an ascending brainstem and descending telencephalic cholecystokinin fiber systems within the striatum and related rostral forebrain areas.

Substantia innominata: a notion which impedes clinical-anatomical correlations in neuropsychiatric disorders.

Comparative neuroanatomical investigations in primates and non-primates have helped disentangle the anatomy of the basal forebrain region known as the substantia innominata. The most striking aspect of this region is its subdivision into two major parts. This reflects the fundamental organizational scheme for this portion of the forebrain. According to this scheme, two major subcortical telencephalic structures, i.e. the striatopallidal complex and extended amygdala, form large diagonally oriented bands. The rostroventral extension of the pallidum accounts for a large part of the rostral subcommissural substantia innominata, while the sublenticular substantia innominata is primarily occupied by elements of the extended amygdala. Also dispersed across this region is the basal nucleus of Meynert, which is part of a more or less continuous collection of cholinergic and non-cholinergic corticopetal and thalamopetal cells, which stretches from the septum diagonal band rostrally to the caudal globus pallidus. The basal nucleus of Meynert is especially prominent in the primate, where it is sometimes inappropriately applied as a synonym for the substantia innominata, thereby tacitly ignoring the remaining components. In most mammals, the extended amygdala presents itself as a ring of neurons encircling the internal capsule and basal ganglia. The extended amygdala may be further subdivided, i.e. into the central extended amygdala (related to the central amygdaloid nucleus) and the medial extended amygdala (related to the medial amygdaloid nucleus), which generally form separate corridors both in the sublenticular region and along the supracapsular course of the stria terminalis. The extended amygdala is directly continuous with the caudomedial shell of the accumbens, and to some extent appears to merge with it. Together the accumbens shell and extended amygdala form an extensive forebrain continuum, which establishes specific neuronal circuits with the medial prefrontal-orbitofrontal cortex and medial temporal lobe. This continuum is particularly characterized by a prominent system of long intrinsic association fibers, and a variety of highly differentiated downstream projections to the hypothalamus and brainstem. The various components of the extended amygdala, together with the shell of the accumbens, are ideally structured to generate endocrine, autonomic and somatomotor aspects of emotional and motivational states. Behavioral observations support this proposition and demonstrate the relevance of these structures to a variety of functions, ranging from the various elements of the reproductive cycle to drug-seeking behavior. The neurochemical and connectional features common to the accumbens shell and the extended amygdala are especially relevant to understanding the etiology and treatment of neuropsychiatric disorders. This is discussed in general terms, and also in specific relation to the neurodevelopmental theory of schizophrenia and to the neurosurgical treatment of neuropsychiatric disorders.

Piecing together the Puzzle of Basal Forebrain Anatomy

The basal forebrain contains a seemingly heterogeneous collection of structures including nucleus accumbens, olfactory tubercle, septum, diagonal band nuclei, bed nucleus of stria terminalis, substantia innominata, olfactory cortex, hippocampus formation and amygdaloid body. It is also traversed by a number of large fiber tracts, e.g. fornix, stria terminalis, diagonal band of Broca, medial forebrain bundle, inferior thalamic peduncle, and ventral amygdalofugal pathway, to which the various basal forebrain structures contribute axons in order to establish connections between themselves and with other parts of the brain. Hypothalamus, the main diencephalic component of the basal forebrain, is one such region closely related to many of the telencephalic basal forebrain structures and fiber tracts. These intimate relations to the hypothalamus provided much of the anatomical rationale to bring the above-mentioned basal forebrain structures together as integral parts of the “limbic system”. This has contributed to the popular view of forebrain organization in which the neocortex is related to the basal ganglia or the “extrapyramidal motor system” through the well-known cortico-striato-pallidal pathways, while so-called limbic structures, e.g. septum, nucleus accumbens, amygdaloid body and allocortical areas like hippocampus and olfactory cortex are characterized foremost by their relation to the hypothalamus, a major regulator of autonomic and endocrine functions.

“Perestroika” in the basal forebrain: Opening the border between neurology and psychiatry

Publisher Summary This chapter focuses on recent advances in the understanding of basal forebrain organization. Such knowledge forms the necessary conceptual framework for physiologic, behavioral, and clinical studies of forebrain functions relevant to neuropsychiatric disorders. Description of the anatomy of the basal forebrain has touched only peripherally on closely related areas of septal and hypothalamic neuronal systems or the many aspects of diffuse ascending brainstem projections. Nevertheless, considering the strategic position of the three basal forebrain systems discussed in the chapter, and the intimate relation that they have with one another and with other parts of the neuraxis, it is not difficult to envision how disruption of the functional integrity of any one of these systems can easily present itself with a multitude of symptoms that show little regard for traditional boundaries of neurologic and psychiatric disciplines.

Chapter 28 Theories of basal forebrain organization and the “emotional motor system”

Publisher Summary This chapter focuses on the neuroanatomy of the heterogenous structures that comprise the basal forebrain, insofar as this territory, together with its most closely associated cortical areas, is likely to provide important projections activating emotionally related motor areas of the brainstem. Special consideration is given to the ventral striatopallidal system and the extended amygdala and areas of transition between these two systems. Many of the structures in the basal forebrain have been included within the various conceptualizations of the limbic system, and the majority of behavioral observations following the early formulations of this concept by Papez and MacLean have generally reinforced the notion that the basal forebrain is systematically involved in the experience and expression of emotions. To some extent, the description of a “descending limbic motor control system” can face difficulties similar to the definition of the “limbic system” at large. The chapter also summarizes the multiple output channels from the basal forebrain to the motor areas of the brainstem.

Efferent connections of the caudal part of the globus pallidus in the rat.

The efferent connections of the caudal pole of the globus pallidus (GP) were examined in the rat by employing the anterograde axonal transport of Phaseolus vulgaris leucoagglutinin (PHA‐L), and the retrograde transport of fluorescent tracers combined with choline acetyltransferase (ChAT) or parvalbumin (PV) immunofluorescence histochemistry. Labeled fibers from the caudal GP distribute to the caudate‐putamen, nucleus of the ansa lenticularis, reuniens, reticular thalamic nucleus (mainly its posterior extent), and along a thin strip of the zona incerta adjacent to the cerebral peduncle. The entopeduncular and subthalamic nuclei do not appear to receive input from the caudal GP. Descending fibers from the caudal GP course in the cerebral peduncle and project to posterior thalamic nuclei (the subparafascicular and suprageniculate nuclei, medial division of the medial geniculate nucleus, and posterior intralaminar nucleus/peripeduncular area) and to extensive brainstem territories, including the pars lateralis of the substantia nigra, lateral terminal nucleus of the accessory optic system, nucleus of the brachium of the inferior colliculus, nucleus sagulum, external cortical nucleus of the inferior colliculus, cuneiform nucleus, and periaqueductal gray. In cases with deposits of PHA‐L in the ventral part of the caudal GP, labeled fibers in addition distribute to the lateral amygdaloid nucleus, amygdalostriatal transition area, cerebral cortex (mainly perirhinal, temporal, and somatosensory areas) and rostroventral part of the lateral hypothalamus.

Quantitative determination of collateral anterior olfactory nucleus projections using a fluorescent tracer with an algebraic solution to the problem of double retrograde labeling

The bilateral projections of the rat anterior olfactory nucleus (AON) were evaluated using retrograde fluorescent tracers. Competitive effects of these tracers led to severe underestimation of bilaterally projecting neurons, when double-labeled cells were counted. The underestimate was corrected using a numerical approach, which is of general utility for problems in double labeling and requires only a single tracer. With this method we estimated that approximately 63% of AON neurons project bilaterally to the olfactory bulbs, except for the external part which projects exclusively to the contralateral olfactory bulb. No other AON neurons project only to the contralateral bulb.

Transition Areas of the Striatopallidal System with the Extended Amygdala in the Rat and Primate: Observations from Histochemistry and Experiments with Mono- and Transsynaptic Tracer

In several papers we have extensively reviewed the concepts of the ventral striatopallidal system and the extended amygdala (de Olmos et al., 1985; Heimer et al., 1985; Alheid and Heimer, 1988; Alheid et al., 1990; Heimer and Alheid, 1991; Heimer et al., 1991a, 1993), and these topics are only briefly recapitulated here. In some of these (e.g. Alheid and Heimer, 1988; Heimer and Alheid, 1991; Heimer et al., 1993) we have pointed out areas where these two structures are difficult to distinguish; these are the problem areas that we wish to confront in this chapter. In some instances, it is clear that the extended amygdala occupies portions of the forebrain normally considered part of the basal ganglia and more speculatively, we believe that some unusual features in other areas of the basal ganglia might reflect some ectopic elements of the extended amygdala.

Temporal lobe lesion-induced obesity in rats: an anatomical investigation of the posterior amygdala and hippocampal formation.

Bilateral lesions centered in the posterodorsal amygdala of female rats resulted in hyperphagia and excessive weight gain (mean = 65.3 g in 20 days compared to 6.8 g for control animals). The brain damage always extended posteriorly into the ventral hippocampal formation. However, lesions that were confined to the ventral hippocampus or amygdalohippocampal area had no effect on daily food intake or body weight, nor did lesions at any other hippocampal site. In a previous study, lesions of the basolateral, corticomedial, and anterior groups of amygdaloid nuclei failed to affect food intake or body weight. It is concluded that the posterodorsal aspect of the amygdala is the critical site for this experimentally induced obesity syndrome. New coordinates for the effective site are presented.

Mapping of transmitter-specific connections: Simultaneous demonstration of anterograde degeneration and changes in the immunostaining pattern induced by lesions

This paper describes simple procedures which allow immunohistochemistry to be combined with a newly developed silver degeneration technique for the purpose of mapping transmitter-specific connections on the light microscopic level. Conditions of fixation, survival time and immunohistochemistry that contribute to optimal results are discussed.