The ventral pallidum (VP) plays a critical role in the processing and execution of motivated behaviors. Yet this brain region is often overlooked in published discussions of the neurobiology of mental health (e.g., addiction, depression). This contributes to a gap in understanding the neurobiological mechanisms of psychiatric disorders. This review is presented to help bridge the gap by providing a resource for current knowledge of VP anatomy, projection patterns and subregional circuits, and how this organization relates to the function of VP neurons and ultimately behavior. For example, ventromedial (VPvm) and dorsolateral (VPdl) VP subregions receive projections from nucleus accumbens shell and core, respectively. Inhibitory GABAergic neurons of the VPvm project to mediodorsal thalamus, lateral hypothalamus, and ventral tegmental area, and this VP subregion helps discriminate the appropriate conditions to acquire natural rewards or drugs of abuse, consume preferred foods, and perform working memory tasks. GABAergic neurons of the VPdl project to subthalamic nucleus and substantia nigra pars reticulata, and this VP subregion is modulated by, and is necessary for, drug-seeking behavior. Additional circuits arise from nonGABAergic neuronal phenotypes that are likely to excite rather than inhibit their targets. These subregional and neuronal phenotypic circuits place the VP in a unique position to process motivationally-relevant stimuli and coherent adaptive behaviors.

The basal forebrain contains several interdigitating anatomical structures, including the diagonal band of Broca, the basal nucleus of Meynert, the ventral striatum, and also cell groups underneath the globus pallidus that bridge the centromedial amygdala to the bed nucleus of the stria terminalis. Among the cell populations, the magnocellular, cholinergic corticopetal projection neurons have received particular attention due to their loss in Alzheimer's disease. In MRI images, the precise delineation of these structures is difficult due to limited spatial resolution and contrast. Here, using microscopic delineations in ten human postmortem brains, we present stereotaxic probabilistic maps of the basal forebrain areas containing the magnocellular cell groups. Cytoarchitectonic mapping was performed in silver stained histological serial sections. The positions and the extent of the magnocellular cell groups within the septum (Ch1-2), the horizontal limb of the diagonal band (Ch3), and in the sublenticular part of the basal forebrain (Ch4) were traced in high-resolution digitized histological sections, 3D reconstructed, and warped to the reference space of the MNI single subject brain. The superposition of the cytoarchitectonic maps in the MNI brain shows the intersubject variability of the various Ch compartments and their stereotaxic position relative to other brain structures. Both the right and left Ch4 regions showed significantly smaller volumes when age was considered as a covariate. Probabilistic maps of compartments of the basal forebrain magnocellular system are now available as an open source reference for correlation with fMRI, PET, and structural MRI data of the living human brain.

Glutamate transmission is critical for controlling cortical activity, but the specific contribution of the different isoforms of vesicular glutamate transporters in subcortical pathways to the neocortex is largely unknown. To determine the distribution and neocortical projections of vesicular glutamate transporter2 (Vglut2)-containing neurons, we used in situ hybridization and injections of the retrograde tracer Fluoro-Gold into the medial prefrontal and primary somatosensory cortices. The thalamus contains the majority of Vglut2 cells projecting to the neocortex (approximately 90% for the medial prefrontal cortex and 96% for the primary somatosensory cortex) followed by the hypothalamus and basal forebrain, the claustrum, and the brainstem. There are significantly more Vglut2 neurons projecting to the medial prefrontal cortex than to the primary somatosensory cortex. The medial prefrontal cortex also receives a higher percentage of Vglut2 projection from the hypothalamus than the primary somatosensory cortex. About 50% of thalamic Vglut2 projection to the medial prefrontal cortex and as much as 80% of the thalamic projection to primary somatosensory cortex originate in various relay thalamic nuclei. The remainder arise from different midline and intralaminar nuclei traditionally thought to provide nonspecific or diffuse projection to the cortex. The extrathalamic Vglut2 corticopetal projections, together with the thalamic intralaminar-midline Vglut2 corticopetal projections, may participate in diffuse activation of the neocortex.

The most prominent feature of the Basal Forebrain (BF) is the collection of large cortically projecting neurons (basal nucleus of Meynert) that serve as the primary source of cholinergic input to the entire cortical mantle. Despite its broad involvement in cortical activation, attention, and memory, the functional details of the BF are not well understood due to the anatomical complexity of the region. This study tested the hypothesis that basalocortical connections reflect cortical connectivity patterns. Distinct retrograde tracers were deposited into various frontal and posterior cortical areas, and retrogradely labeled cholinergic and noncholinergic neurons were mapped in the BF. Concurrently, we mapped retrogradely labeled cells in posterior cortical areas that project to various frontal areas, and all cell populations were combined in the same coordinate system. Our studies suggest that the cholinergic and noncholinergic projections to the neocortex are not diffuse, but instead, are organized into segregated or overlapping pools of projection neurons. The extent of overlap between BF populations projecting to the cortex depends on the degree of connectivity between the cortical targets of these projection populations. We suggest that the organization of projections from the BF may enable parallel modulation of multiple groupings of interconnected yet nonadjacent cortical areas.

We have examined the location of cholinergic and GABAergic neurons that project to the rat main olfactory bulb by combining choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) immunohistochemistry with retrograde fluorescent tracing. Since many of the projection neurons are located in subcortical basal forebrain structures, where the delineation of individual regions is difficult, particular care was taken to localize projection neurons with respect to such landmarks as the ventral pallidum (identified on the basis of GAD immunoreactivity), the diagonal band, and medial forebrain bundle. In addition, sections with fluorescent tracers or immunofluorescence were counterstained for Nissl substance in order to correlate tracer or immunopositive neurons with the cytoarchitecture of the basal forebrain. The majority of the cholinergic bulbopetal neurons are located in the medial half of the nucleus of the horizontal limb of the diagonal band (HDB), whereas only a few are located in its lateral half. A substantial number of cholinergic bulbopetal cells are also found in the sublenticular substantia innominata. A small number of cholinergic bulbopetal neurons, finally, are located in the ventrolateral portion of the nucleus of the vertical limb of the diagonal band. At the level of the crossing of the anterior commissure, approximately 17% of the bulbopetal neurons in the HDB are ChAT-positive. The noncholinergic bulbopetal cells are located mainly in the lateral half of the HDB. GAD-containing bulbopetal neurons are primarily located in the caudal part of the HDB, especially in its lateral part. About 30% of the bulbopetal projection neurons in the HDB are GAD-positive. A few GAD-positive bulbopetal cells, furthermore, are located in the ventral pallidum, anterior amygdaloid area, deep olfactory cortex, nucleus of the lateral olfactory tract, lateral hypothalamic area, and tuberomamillary nucleus. The topography of bulbopetal neurons was compared to other projection neurons in the HDB. After multiple injections of fluorescent tracer in the neocortex, retrogradely labeled neurons were concentrated in the most medial part of the HDB, while neurons projecting to the olfactory and entorhinal cortices were located in the ventral part of the HDB. These results show that the cells of the HDB can be divided into subpopulations based upon projection target as well as transmitter content. Furthermore, these subpopulations correspond, at least to a considerable extent, to areas that can be defined on cyto- and fibroarchitectural grounds.

The medial septum, diagonal bands, ventral pallidum, substantia innominata, globus pallidus, and internal capsule contain a heterogeneous population of neurons, including cholinergic and noncholinergic (mostly GABA containing), corticopetal projection neurons, and interneurons. This highly complex brain region, which constitutes a significant part of the basal forebrain has been implicated in attention, motivation, learning, as well as in a number of neuropsychiatric disorders, such as Alzheimer's disease, Parkinson's disease, and schizophrenia. Part of the difficulty in understanding the functions of the basal forebrain, as well as the aberrant information-processing characteristics of these disease states lies in the fact that the organizational principles of this brain area remained largely elusive. On the basis of new anatomical data, it is proposed that a large part of the basal forebrain corticopetal system be organized into longitudinal bands. Considering the topographic organization of cortical afferents to different divisions of the prefrontal cortex and a similar topographic projection of these prefrontal areas to basal forebrain regions, it is suggested that several functionally segregated cortico-prefronto-basal forebrain-cortical circuits exist. It is envisaged that such specific "triangular" circuits could amplify selective attentional processing in posterior sensory cortical areas.

No abstract

Summary Basal forebrain cholinergic neurons influence cortical state, plasticity, learning and attention. They collectively innervate the entire cerebral cortex, differentially controlling acetylcholine efflux across different cortical areas and timescales. Such control might be achieved by differential inputs driving separable cholinergic outputs, although no input-output relationship on a brain-wide level has ever been demonstrated. Here we identify input neurons to cholinergic cells projecting to specific cortical regions by infecting cholinergic axon terminals with a monosynaptically-restricted viral tracer. This approach revealed several circuit motifs, such as central amygdala neurons synapsing onto basolateral amygdala-projecting cholinergic neurons or strong somatosensory cortical input to motor cortex-projecting cholinergic neurons. The presence of input cells in the parasympathetic midbrain nuclei contacting frontally projecting cholinergic neurons suggest that the network regulating the inner eye muscles are additionally regulating cortical state via acetylcholine efflux. This dataset enables future circuit-level experiments to identify drivers of known cholinergic cortical functions.