A role for spindles in the onset of rapid eye movement sleep.

Sleep spindle generation classically relies on an interplay between the thalamic reticular nucleus (TRN), thalamo-cortical (TC) relay cells and cortico-thalamic (CT) feedback during non-rapid eye movement (NREM) sleep. Spindles are hypothesized to stabilize sleep, gate sensory processing and consolidate memory. However, the contribution of non-sensory thalamic nuclei in spindle generation and the role of spindles in sleep-state regulation remain unclear. Using multisite thalamic and cortical LFP/unit recordings in freely behaving mice, we show that spike-field coupling within centromedial and anterodorsal (AD) thalamic nuclei is as strong as for TRN during detected spindles. We found that spindle rate significantly increases before the onset of rapid eye movement (REM) sleep, but not wakefulness. The latter observation is consistent with our finding that enhancing spontaneous activity of TRN cells or TRN-AD projections using optogenetics increase spindle rate and transitions to REM sleep. Together, our results extend the classical TRN-TC-CT spindle pathway to include non-sensory thalamic nuclei and implicate spindles in the onset of REM sleep.

A New Projection From the Deep Cerebellar Nuclei to the Hippocampus via the Ventrolateral and Laterodorsal Thalamus in Mice.

The cerebellar involvement in cognitive functions such as attention, language, working memory, emotion, goal-directed behavior and spatial navigation is constantly growing. However, an exact connectivity map between the hippocampus and cerebellum in mice is still unknown. Here, we conducted a tracing study to identify the sequence of transsynaptic, cerebellar-hippocampal connections in the mouse brain using combinations of Recombinant adeno-associated virus (rAAV) and pseudotyped deletion-mutant rabies (RABV) viruses. Stereotaxic injection of a primarily anterograde rAAV-WGA (wheat germ agglutinin)-Cre tracer virus in the deep cerebellar nuclei (DCN) of a Cre-dependent tdTomato reporter mouse resulted in strong tdTomato labeling in hippocampal CA1 neurons, retrosplenial cortex (RSC), rhinal cortex (RC) as well as thalamic and cerebellar areas. Whereas hippocampal injections with the retrograde tracer virus rAAV-TTC (tetanus toxin C fragment)-eGFP, displayed eGFP positive cells in the rhinal cortex and subiculum. To determine the sequence of mono-transsynaptic connections between the cerebellum and hippocampus, we used the retrograde tracer RABVΔG-eGFP(EnvA). The tracing revealed a direct connection from the dentate gyrus (DG) in the hippocampus to the RSC, RC and subiculum (S), which are monosynaptically connected to thalamic laterodorsal and ventrolateral areas. These thalamic nuclei are directly connected to cerebellar fastigial (FN), interposed (IntP) and lateral (Lat) nuclei, discovering a new projection route from the fastigial to the laterodorsal thalamic nucleus in the mouse brain. Collectively, our findings suggest a new cerebellar-hippocampal connection via the laterodorsal and ventrolateral thalamus to RSC, RC and S. These results strengthen the notion of the cerebellum's involvement in cognitive functions such as spatial navigation via a polysynaptic circuitry.

Cerebellar projections to the ventral lateral geniculate nucleus and the thalamic reticular nucleus in the cat.

The ventral lateral geniculate nucleus (LGNv) is a retinorecipient part of the ventral thalamus and in cats, it consists of medial (M), medial intermediate (IM), lateral intermediate (IL), lateral (L), and dorsal (D) subdivisions. These subdivisions can be differentiated not only by their cytoarchitecture, but also by their connectivity and putative functions. The LGNv may play a role in visuomotor gating, in that there is evidence of cerebellar afferent projections to the intermediate subdivisions. The cerebellar posterior interpositus (IP) and lateral (LC) nuclei are known to project to IM and IL, but the specifics of these projections are unclear. We hypothesized that the IP and LC project differentially to IM and IL. To evaluate LGNv innervation by the deep cerebellar nuclei, we injected the tract-tracer wheat germ agglutinin-horseradish peroxidase (WGA-HRP) into several different regions of the LGNv and cerebellar nuclei of adult cats in either sex. Small injections into the middle and posterior LGNv retrogradely labeled cells in the ventral part of the IP. However, injections in the anterior regions of the LGNv, with or without diffusion into the thalamic reticular nucleus (Re), retrogradely labeled cells in the ventral part of both the IP and the LC. Confirmatory injections into the IP and LC produced terminal-like labeling distributed in IM, IL, and Re; injections mostly localized to the LC resulted in labeling mainly in IM and Re. We concluded that the IP projects to IL whereas the LC projects to IM and Re.

Different distributions of calbindin and calretinin immunostaining across the medial and dorsal divisions of the mouse medial geniculate body.

We studied the distributions of calretinin and calbindin immunoreactivity in subdivisions of the mouse medial geniculate body and the adjacent paralaminar nuclei. We found that the vast majority of labeled cells in the dorsal division of the medial geniculate body were immunoreactive for calbindin-only, whereas most of the remaining labeled cells were double-labeled. Very few calretinin+ only cells were observed. By contrast, we observed significant proportions of calbindin+ only, calretinin+ only and double-labeled cells in the medial division of the medial geniculate body. Further, the distributions of calbindin-only, calretinin-only and double-labeled cells did not differ between the medial division of the medial geniculate body, the suprageniculate nucleus, the peripeduncular nucleus and the posterior intralaminar nucleus. We found essentially no somatic staining for either calbindin or calretinin in the ventral division of the medial geniculate body. These data suggest that there are distinct neurochemical differences between the two non-lemniscal auditory thalamic nuclei. In addition, these data extend previous observations that the medial division of the medial geniculate body shares many properties with the paralaminar group of nuclei.

Thalamic damage in periventricular leukomalacia: novel pathologic observations relevant to cognitive deficits in survivors of prematurity.

Despite major advances in the long-term survival of premature infants, cognitive deficits occur in 30-50% of very preterm (<32 gestational weeks) survivors. Impaired working memory and attention despite average global intelligence are central to the academic difficulties of the survivors. Periventricular leukomalacia (PVL), characterized by periventricular necrosis and diffuse gliosis in the cerebral white matter, is the major brain pathology in preterm infants. We tested the novel hypothesis that pathology in thalamic nuclei critical for working memory and attention, i.e. mediodorsal nucleus and reticular nucleus, respectively, occurs in PVL. In 22 PVL cases (gestational age 32.5 +/- 4.8 wk) and 16 non-PVL controls (36.7 +/- 5.2 wk) who died within infancy, the incidence of thalamic pathology was significantly higher in PVL cases (59%; 13/22) compared with controls (19%; 3/16) (p = 0.01), with substantial involvement of the mediodorsal, and reticular nuclei in PVL. The prevention of thalamic damage may be required for the eradication of defects in survivors with PVL.

Demonstration of a trigeminothalamic pathway to the oval paracentral intralaminar thalamic nucleus and its involvement in the processing of noxious orofacial deep inputs.

Using combined retrograde labeling and Fos protein immunohistochemistry, we show that after masseter inflammation, a population of neurons in the dorsal portion of the subnuclei interpolaris/caudalis transition zone at the level of the obex was activated and projected to the oval paracentral nucleus (OPC) of the intralaminar thalamic nuclei. The present findings indicate a trigeminothalamic pathway to the OPC intralaminar nucleus involved in central processing of orofacial deep noxious input.

A maternal blood-borne factor promotes survival of the developing thalamus.

In this report, we describe the identification of a polypeptide survival-promoting factor that is produced by maternal and early postnatal peripheral blood mononuclear cells (PBMCs) of the immune system in Long-Evans rats and humans. The factor, termed Y-P30, most likely arises from proteolytic processing of a larger precursor protein and accumulates mainly in pyramidal neurons of the developing cortex and hippocampus but not in astrocytes. It was released from neurons grown in culture and substantially promotes survival of cells in explant monocultures of perinatal thalamus from the offspring. Y-P30 mRNA was not detectable in infant or adult brain and was present only in blood cells of pregnant rats and humans but not in nonpregnant controls. However, Y-P30 transcription could be induced in PBMCs of adult animals by a central nervous system lesion (i.e., optic nerve crush), which points to a potential role of the factor not only in neuronal development but also in neuroinflammation after white matter injury.

Differential distribution of the KCl cotransporter KCC2 in thalamic relay and reticular nuclei.

In the thalamus of the rat the reversal potential of GABA-induced anion currents is more negative in relay cells than in neurones of the reticular nucleus (nRt) due to different chloride extrusion mechanisms operating in these cells. The distribution of KCl cotransporter type 2 (KCC2), the major neuronal chloride transporter that may underlie this effect, is unknown in the thalamus. In this study the precise regional and ultrastructural localization of KCC2 was examined in the thalamus using immunocytochemical methods. The neuropil of all relay nuclei was found to display intense KCC2 immunostaining to varying degrees. In sharp contrast, the majority of the nRt was negative for KCC2. In the anterior and dorsal part of the nRt, however, KCC2 immunostaining was similar to relay nuclei and parvalbumin and calretinin were found to colocalize with KCC2. At the ultrastructural level, KCC2 immunoreactivity was mainly located in the extrasynaptic membranes of thick and thin dendrites and the somata of relay cells but was also found in close association with asymmetrical synapses formed by cortical afferents. Quantitative evaluation of KCC2 distribution at the electron microscopic level demonstrated that the density of KCC2 did not correlate with dendritic diameter or synaptic coverage but is 1.7 times higher on perisynaptic membrane surfaces than on extrasynaptic membranes. Our data demonstrate that the regional distribution of KCC2 is compatible with the difference in GABA-A reversal potential between relay and reticular nuclei. At the ultrastructural level, abundant extrasynaptic KCC2 expression will probably play a role in the regulation of extrasynaptic GABA-A receptor-mediated inhibition.

Three-dimensional proton spectroscopy of deep gray matter nuclei in relapsing-remitting MS.

The metabolic changes in the deep gray matter (GM) nuclei, thalamus, and basal ganglia of patients with relapsing-remitting multiple sclerosis were investigated with quantitative, multivoxel, three-dimensional proton MR spectroscopy. This technique facilitated the study of several bilateral structures in a single session at sub-cubic centimeter spatial resolution. Compared with 9 matched control subjects, the deep GM nuclei of 11 patients showed 7% lower N-acetylaspartate and 14% higher choline levels (p = 0.02 for both).

Rat intralaminar thalamic nuclei projections to the globus pallidus: a biotinylated dextran amine anterograde tracing study.

The topographical organization and ultrastructural features of the intralaminar thalamic nuclei (ITN) projections to the globus pallidus (GP) were studied using the biotinylated dextran amine (BDA) anterograde tracing method in the rat. To assess the functional association of BDA injection sites in the ITN, the known topographical organization of the ITN-neostriatal (Str) projections and calcium binding protein (CaBP) immunostaining patterns of the Str and GP were used. BDA injection in the lateral part of the lateral parafascicular nucleus and the caudal part of the central lateral nucleus labeled fibers and boutons mainly in the dorsolateral sensorimotor territory of the Str and the middle territories of the GP. BDA injection in the medial part of the lateral parafascicular nucleus and the central lateral nucleus labeled mainly the middle association territory of the Str and the border and the caudomedial territories of the GP. BDA injection in the medial parafascicular nucleus and the central medial nucleus labeled mainly the medial limbic territory of the Str. The medial parafascicular nucleus projected to the medial-most region of the GP, while the central medial nucleus projection to the GP was very sparse. Electron microscopic observations indicated that BDA-labeled boutons form asymmetric synapses mainly on 0.5-2.0 microm diameter dendritic shafts in the GP. The boutons were small but had a relatively long active zone. The present observations together with the known topographical organization of striatopallidal projections indicated that the ITN-GP projections were topographically organized in parallel to the ITN-Str projections. Thus, each part of the ITN projecting to the sensorimotor, the association, and the limbic territories of the Str also projects to the corresponding functional territories of the GP.

Widespread thalamic terminations of fibers arising in the superficial medullary dorsal horn of monkeys and their relation to calbindin immunoreactivity.

The relay of pain fibers from the spinal and medullary dorsal horn in the thalamus has become a controversial issue. This study analyzed the relationship of fibers arising in lamina I to nuclei in and around the caudal pole of the ventral posterior nuclear complex and especially to a zone of calbindin-dense immunoreactivity (VMpo) identified by some authors as the sole thalamic relay for these fibers. We show that the densest zone of calbindin immunoreactivity is part of a more extensive, calbindin-immunoreactive region that lies well within the medial tip of the ventral posterior medial nucleus (VPM), as delineated by other staining methods, and prove that the use of different anti-calbindin antibodies cannot account for differences in interpretations of the organization of the posterior thalamic region. By combining immunocytochemical staining with anterograde tracing from injections involving lamina I, we demonstrate widespread fiber terminations that are not restricted to the calbindin-rich medial tip of VPM and show that the lamina I arising fibers are not themselves calbindin immunoreactive. This study disproves the existence of VMpo as an independent thalamic pain nucleus or as a specific relay in the ascending pain system.

Immunohistochemistry and neural connectivity of the Ov shell in the songbird and their evolutionary implications.

The neuropeptide immunohistochemistry and neural connectivity of areas surrounding the thalamic auditory nucleus (the nucleus ovoidalis [Ov]), as well as the areas to which it is connected, were investigated in a songbird, the Bengalese finch. The results showed that met-enkephalin was present in the Ov shell and most of the areas connected to it, but not in the Ov core. Anterograde and retrograde tracing studies showed that the Ov shell was more widely connected than the Ov core. The Ov shell was mainly connected to: 1). areas flanking the primary telencephalic auditory field (i.e., fields L2b, L1, and L3) and areas surrounding the robust nucleus of the archistriatum (RA); 2). several hypothalamic areas such as the nucleus ventromedialis hypothalami (VMN) and the nucleus anterior medialis hypothalami (AM). Some of these areas connected to the Ov shell are thought to be involved in auditory mediated neurosecretory activities. These results, which are similar to those reported previously in non-songbirds, suggest that the Ov shell and other surrounding areas of auditory and song-control nuclei are conserved in birds. These findings are discussed in terms of the evolution of the core-and-surround organization of auditory and song-control nuclei.

Immunohistochemical localization of the voltage-gated potassium channel subunit Kv1.4 in the central nervous system of the adult rat.

A large set of voltage-gated potassium channels is involved in regulating essential aspects of neuronal function in the central nervous system, thus contributing to the ability of neurons to respond to a given input. In the present study, we used immunocytochemical methods to elucidate the regional, cellular and subcellular distribution of the voltage-gated potassium channel subunit Kv1.4, a member of the Shaker subfamily, in the brain. At the light microscopic level, the Kv1.4 subunit showed a unique distribution pattern, being localized in specific neuronal populations of the rat brain. The neuronal regions expressing the highest levels of Kv1.4 protein included the cerebral cortex, the hippocampus, the posterolateral and posteromedial ventral thalamic nuclei, the dorsolateral and medial geniculate nuclei, the substantia nigra and the dorsal cochlear nucleus. The Kv1.4 subunit was also present in other neuronal populations, with different levels of Kv1.4 immunoreactivity. In all immunolabeled regions, the Kv1.4 subunit was mostly diffusely distributed and, to a lesser extent, it stained cell bodies and proximal dendrites. Furthermore, Kv1.4 immunoreactivity was also detected in nerve terminals and axonal terminal fields. At the electron microscopic level, Kv1.4 was located postsynaptically in dendritic spines and shafts at extrasynaptic sites, as well as presynaptically in axon and active zone of axon terminals, in the neocortex and hippocampus. The findings indicate that Kv1.4 channels are widely distributed in the rat brain and suggest that activation of this channel would have different modulatory effects on neuronal excitability.

[The localization and the sexual differences of substance P in vocal control and part auditory nuclei of Carduelis spinus].

The expression of substance P in the vocal control and auditory nuclei was investigated by wsing immunohistochemical methods, and the gray density of numerical value was measured with the image processing system in females and males of Carduelis spinus. Then, the distribution and the gray density of substance P were compared between males and females. The results indicate that: 1) Substance P labeled terminal and part cells were distributed in the Area X; 2) Substance P labeled cells were distributed in the nucleus high vocal center (HVc), magnocellular nucleus of the anterior neostriatum (MAN), robust nucleus of the archistriatum (RA) and dorsolateral nucleus of the anterior thalamus (DLM); 3) Substance P labeled terminal and fibers were distributed in the vocal control nuclei such as nucleus dorsalis medialis (DM) and the nucleus hypoglossi, pars tracheosyringealis (nXI-Its), and in the auditory nuclei such as the nucleus ovidalisashell (Ov shell), the shell regions of mesencephalicus lateralis, pars dorsalis (MLd shell) and the nucleus intercollicularis (ICo). The values of gray degree of substance P labeled cells or fibers were significantly higher in males than that in females. The present study indicates that the distribution of substance P exhibits significantly sexual difference in the songbird. The presence of substance P in most auditory and vocal control nuclei suggests that substance P may play an important physiological role in the auditory perception and vocal production.

Deficit of endogenous kynurenic acid in the frontal cortex of rats with a genetic form of absence epilepsy.

The present studies sought to determine the concentrations of endogenous kynurenic acid (KYNA) and to measure the activity of kynurenine aminotransferases (KAT) I and II in the discrete brain regions of 3- and 6-month old WAG/Rij rats, a genetic model of absence epilepsy. Analogues experiments were performed using age-matched ACI rats, which served as a non-epileptic control. The age-dependent increase in KYNA concentration in the frontal cortex of WAG/Rij rats was considerably reduced in comparison to what was found in ACI rats. Consequently, the concentration of KYNA in the frontal cortex of epileptic rats was significantly lower than in non-epileptic controls. There were no such strain differences in other brain regions. The activities of KAT I and II also showed age-dependent increase with an exception for KAT II in the frontal cortex. Our data suggest that selective deficits of endogenous KYNA may account for increased excitability in the frontal cortex, which in turn may lead to the development of spontaneous spike-wave discharges in WAG/Rij rats.

An optimized method for simultaneous demonstration of neurons and myelinated fiber tracts for delineation of individual trunco- and palliothalamic nuclei in the mammalian brain.

The truncothalamic complex has long been considered to be a nuclear group with "non-specific" projections. More recently, it is suggested that these thalamic nuclei play an important role in regulating distinct basal ganglia circuits. To further analyze the exact biological function of individual nuclei of the truncothalamic complex a simple and reliable technique for an exact delineation of distinct nuclei is desirable. Therefore, we evaluated and optimized several potential procedures for a combined visualization of neurons and myelinated fibers. Fiber staining with gold toning or immunocytochemical visualization of myelin basic protein shows high contrast and precision but precludes sufficient demonstration of neuronal cell bodies. When the most common technique for the simultaneous visualization of both structures, the Kluver-Barrera procedure, is used, demonstration of myelinated fibers is restricted when the technique is applied to cryostat or vibratome sections. In the present report this limitation was abolished. The final protocol includes lipid extraction prior to the incubation with Luxol Fast Blue and uses carefully characterized staining conditions for Luxol Fast Blue and cresyl violet rendering microscopically controlled differentiation steps unnecessary. The optimized Kluver-Barrera technique results in high precision localization of individual axons and cell bodies and thus permits an exact and simple delineation of individual nuclei in the vertebrate thalamus.

Parvalbumin and GABA in the developing somatosensory thalamus of the rat: an immunocytochemical ultrastructural correlation.

The calcium binding protein parvalbumin (PV) is widely distributed in the mammalian nervous system and its relationship with GABAergic neurons differs within thalamic nuclei and animal species. In the rat somatosensory thalamus PV immunoreactive (ir) neurons were found only in the GABAergic reticular thalamic nucleus (RT), while a dense PVir neuropil is present in the ventrobasal complex (VB). In this study the distribution and relationship of PV and GABA were investigated in RT and VB during postnatal development at electron microscopic level. The pre-embedding immunoperoxidase detection of PV was combined with the post-embedding immunogold localization of GABA. In RT, at all developmental ages, neuronal cell bodies, dendrites and rare axonal terminals were both PVir and GABAir. In VB during the first postnatal week several small vesicle-containing profiles were double-labelled and some of them were identifiable as synaptic terminals. From postnatal day 7 (P7) to P9 the medial part of VB was more intensely PVir than the lateral one and some differences in the sequence of maturation of PVir terminals were noted between these two VB subdivisions. Single-labelled PVir profiles were first observed at P8, whereas single-labelled PVir terminals appeared at P12 and at P15 they became more frequent and larger, showing the typical morphology of ascending afferents described in adult VB. These results demonstrate the late expression of PV and acquisition of adult morphology in ascending terminals of rat VB during postnatal development in comparison with the innervation arising from the GABAergic RT.

The distribution of calbindin, calretinin and parvalbumin immunoreactivity in the human thalamus.

UNLABELLED: Calcium-binding proteins show a heterogeneous distribution in the mammalian central nervous system and are useful markers for identifying neuronal populations. The distribution of the three major calcium-binding proteins - calbindin-D28k (calbindin), calretinin and parvalbumin - has been investigated in eight neurologically normal human thalami using standard immunohistochemical techniques. Most thalamic nuclei show immunoreactive cell bodies for at least two of the three calcium-binding proteins; the only nucleus showing immunoreactivity for one calcium-binding protein is the centre médian nucleus (CM) which is parvalbumin-positive. Overall, the calcium-binding proteins show a complementary staining pattern in the human thalamus. In general terms, the highest density of parvalbumin staining is in the component nuclei of the ventral nuclear group (i.e. in the ventral anterior, ventral lateral and ventral posterior nuclear complexes) and in the medial and lateral geniculate nuclear groups. Moderate densities of parvalbumin staining are also present in regions of the mediodorsal nucleus (MD). By contrast, calbindin and calretinin immunoreactivity both show a similar distribution of dense staining in the thalamus which appears to complement the pattern of intense parvalbumin staining. That is, calbindin and calretinin staining is most dense in the rostral intralaminar nuclear group and in the patchy regions of the MD which show very low levels of parvalbumin staining. However, calbindin and calretinin also show low levels of staining in the ventral nuclear complex and in the medial and lateral geniculate bodies which overlaps with the intense parvalbumin staining in these regions. These results show that the calcium-binding proteins are heterogeneously distributed in a complementary fashion within the nuclei of the human thalamus. They provide further support for the concept recently proposed by Jones (Jones, E.G., 1998. VIEWPOINT: the core and matrix of thalamic organization. Neuroscience 85, 331-345) that the primate thalamus comprises of a matrix of calbindin immunoreactive cells and a superimposed core of parvalbumin immunoreactive cells which may have differential patterns of cortical projections.

Neurochemical changes after morphine, dizocilpine or riluzole in the ventral posterolateral thalamic nuclei of rats with hyperalgesia.

A number of studies suggest the involvement of glutamate in central hyperalgesia through NMDA receptors in animal models of inflammation. Most studies analyze glutamate effects at the spinal cord level. In this work, the effects of morphine, dizocilpine and riluzole on the hyperalgesia induced by carrageenan administration in the rat paw model were investigated. The effects of morphine and riluzole on the release of glutamate and aspartate and on the concentrations of citrulline and arginine in dialysates of the ventral posterolateral nucleus of the thalamus were also examined. All three drugs decreased hyperalgesia when administered prior to carrageenan injection. Morphine decreased the glutamate concentration in dialysates of the ventral posterolateral nucleus but did not affect the concentrations of the other amino acids. The effect of morphine was observed in the absence of painful stimulation and when pressure applied to the rat paw induced a nociceptive reaction. Riluzole decreased the concentrations of glutamate and aspartate and those of citrulline and arginine in the presence or absence of painful stimulation. These experiments suggest that morphine and riluzole attenuate the hyperalgesia induced by injection of carrageenan in the rat hind paw, at least partly, by decreasing glutamate release in the ventral posterolateral thalamic nucleus.

Localization of nicotinic receptor subunit mRNAs in monkey brain by in situ hybridization.

Nicotinic receptors are implicated in memory, learning, locomotor activity, and addiction. Identification of the specific receptor subtypes that mediate these behaviors is essential for understanding their role in central nervous system (CNS) function. Although expression of nicotinic receptor transcript has been studied in rodent brain, their localization in the monkey CNS, which may be a better model for the human brain, is not yet known. We therefore investigated the distribution of alpha4, alpha6, alpha7, beta2, beta3, and beta4 receptors subunit mRNAs in the monkey brain by using in situ hybridization. alpha4 and alpha7 mRNAs were very widely expressed, with a substantial degree of overlap in their distribution, except for the reticular nucleus of the thalamus in which alpha7 mRNA was much more prominently expressed. beta2 and beta4 mRNA were also widely distributed, although beta4 was more prominently localized in thalamic nuclei than beta2. The distribution of alpha6 and beta3 mRNA was very distinct from that of the other transcripts, being restricted to catecholaminergic nuclei, the cerebellum, and a few other areas. Although there were similarities in distribution of the nicotinic receptor subunit mRNAs in monkey and rodent brain, there were prominent differences in areas such as the caudate, putamen, locus coeruleus, medial habenula, and cerebellum. In fact, the distribution of alpha4 and alpha7 mRNAs in the monkey caudate and putamen was more similar to that reported in the human than rodent brain. These findings have implications for the development of drug therapies for neurological disorders, such as Alzheimer's and Parkinson's disease, in which nicotinic receptors are decreased.