GABAergic and other noncholinergic basal forebrain neurons,together with cholinergic neurons,project to the mesocortex and isocortex in the rat

The extrathalamic relay from the brainstem reticular formation to the cerebral cortex in the basal forebrain has been thought to be constituted predominantly, if not exclusively, by cholinergic neurons. In contrast, the septohippocampal projection has been shown to contain an important contingent of γ-aminobutyric acid (GABA)ergic neurons. In the present study, we investigated whether GABAergic neurons also contribute to the projection from the basal forebrain to neocortical regions, including the mesocortex (limbic) and the isocortex in the rat. For this purpose, retrograde transport of cholera toxin (CT) was examined from the medial prefrontal cortex for the mesocortex and from the parietal cortex for the isocortex and was combined with dual-immunohistochemical staining for either choline acetyltransferase (ChAT) or glutamic acid decarboxylase (GAD) in adjacent series of sections. Retrogradely labelled GAD⁺ neurons were codistributed with retrogradely labelled ChAT⁺ neurons through the basal forebrain from both the prefrontal and the parietal cortex, suggesting parallel, widespread cortical projections. The GAD⁺ cortically projecting cells were similar in size to the ChAT⁺ cells, thereby indicating that they comprise a contingent of the magnocellular basal cell complex. The proportions of retrogradely labelled neurons that were GAD⁺ (approximately one-third) were equal to or greater than those that were ChAT⁺ from both the prefrontal cortex and the parietal cortex. In addition, the total of GAD⁺ and ChAT⁺ neurons did not account for the total number of cortically projecting cells, indicating that another equivalent proportion of chemically unidentified noncholinergic neurons also contributes to the basalocortical projection. Accordingly, as in the allocortex, GABAergic, cholinergic, and other unidentified noncholinergic neurons may have the capacity to modulate activity in the mesocortex (limbic) and the isocortex through parallel, widespread projections. J. Comp. Neurol. 383:163-177, 1997. © 1997 Wiley-Liss, Inc.     

Synaptic organization of projections from basal forebrain structures to the mediodorsal thalamic nucleus of the rat.

The synaptic organization of the mediodorsal thalamic nucleus (MD) in the rat was studied with the electron microscope, and correlated with the termination of afferent fibers labeled with wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP). Presynaptic axon terminals were classified into four categories in MD on the basis of the size, synaptic vesicle morphology, and synaptic membrane specializations: 1) small axon terminals with round synaptic vesicles (SR), which made asymmetrical synaptic contacts predominantly with small dendritic shafts; 2) large axon terminals with round vesicles (LR), which established asymmetrical synaptic junctions mainly with large dendritic shafts; 3) small to medium axon terminals with pleomorphic vesicles (SMP), which formed symmetrical synaptic contacts with somata and small-diameter dendrites; 4) large axon terminals with pleomorphic vesicles (LP), which made symmetrical synaptic contacts with large dendritic shafts. Synaptic glomeruli were also identified in MD that contained either LR or LP terminals as the central presynaptic components. No presynaptic dendrites were identified. In order to identify terminals arising from different sources, injections of WGA-HRP were made into cortical and subcortical structures known to project to MD, including the prefrontal cortex, piriform cortex, amygdala, ventral pallidum and thalamic reticular nucleus. Axons from the amygdala formed LR terminals, while those from the prefrontal and insular cortex ended exclusively in SR terminals. Fibers labeled from the piriform cortex formed both LR and SR endings. Based on their morphology, all of these are presumed to be excitatory. In contrast, the axons from the ventral pallidum ended as LP terminals, and those from the thalamic reticular nucleus formed SMP terminals. Both are presumed to be inhibitory. At least some terminals from these sources have also been identified as GABAergic, based on double labeling with anterogradely transported WGA-HRP and glutamic acid decarboxylase (GAD) immunocytochemistry.     

Calretinin immunoreactivity in the brain of the zebrafish, Danio rerio: distribution and comparison with some neuropeptides and neurotransmitter-synthesizing enzymes. I. Olfactory organ and forebrain

The distribution of calretinin (CR) in the forebrain and the olfactory system of the adult zebrafish was studied by using immunocytochemical techniques. Previous studies in trout forebrain have indicated that CR-immunoreactive neurons acquire this phenotype rather early in development (Castro et al., J. Comp. Neurol. 467:254-269, 2003). Thus, precise knowledge of CR-expressing neuronal populations in adult zebrafish may help to decipher late stages of forebrain morphogenesis. For analysis of some forebrain nuclei and regions, CR distribution was compared with that of various ancillary markers: choline acetyltransferase, glutamic acid decarboxylase, tyrosine hydroxylase, neuropeptide Y, thyrotropin-releasing hormone, and galanin. The results reveal that calretinin is a specific marker of olfactory receptor neurons and of various neuronal populations distributed throughout the telencephalon and diencephalon. In addition, CR immunocytochemistry revealed characteristic patterns of fibers and neuropil in several telencephalic and diencephalic regions, indicating that it is a useful marker for characterizing a number of neural centers, pathways, and neuronal subpopulations in the zebrafish forebrain. Some ancillary markers also showed a distinctive distribution in pallial and subpallial regions, revealing additional aspects of forebrain organization. Comparison of the distribution of CR observed in the forebrain of zebrafish with that reported in other teleosts revealed a number of similarities and also some interesting differences. This indicates that various neuronal populations have maintained the CR phenotype in widely divergent teleost lines and suggests that CR studies may prove very useful for comparative analysis.     

Distribution and intrinsic membrane properties of basal forebrain GABAergic and parvalbumin neurons in the mouse

The basal forebrain (BF) strongly regulates cortical activation, sleep homeostasis, and attention. Many BF neurons involved in these processes are GABAergic, including a subpopulation of projection neurons containing the calcium‐binding protein, parvalbumin (PV). However, technical difficulties in identification have prevented a precise mapping of the distribution of GABAergic and GABA/PV+ neurons in the mouse or a determination of their intrinsic membrane properties. Here we used mice expressing fluorescent proteins in GABAergic (GAD67‐GFP knock‐in mice) or PV+ neurons (PV‐Tomato mice) to study these neurons. Immunohistochemical staining for GABA in GAD67‐GFP mice confirmed that GFP selectively labeled BF GABAergic neurons. GFP+ neurons and fibers were distributed throughout the BF, with the highest density in the magnocellular preoptic area (MCPO). Immunohistochemistry for PV indicated that the majority of PV+ neurons in the BF were large (>20 μm) or medium‐sized (15–20 μm) GFP+ neurons. Most medium and large‐sized BF GFP+ neurons, including those retrogradely labeled from the neocortex, were fast‐firing and spontaneously active in vitro. They exhibited prominent hyperpolarization‐activated inward currents and subthreshold “spikelets,” suggestive of electrical coupling. PV+ neurons recorded in PV‐Tomato mice had similar properties but had significantly narrower action potentials and a higher maximal firing frequency. Another population of smaller GFP+ neurons had properties similar to striatal projection neurons. The fast firing and electrical coupling of BF GABA/PV+ neurons, together with their projections to cortical interneurons and the thalamic reticular nucleus, suggest a strong and synchronous control of the neocortical fast rhythms typical of wakefulness and REM sleep. J. Comp. Neurol., 521:1225–1250, 2013. © 2012 Wiley Periodicals, Inc.     

Organization of the avian “corticostriatal” projection system: A retrograde and anterograde pathway tracing study in pigeons

Birds have well-developed basal ganglia within the telencephalon, including a striatum consisting of the medially located lobus parolfactorius (LPO) and the laterally located paleostriatum augmentatum (PA), Relatively little is known, however, about the extent and organization of the telencephalic “cortical” input to the avian basal ganglia (i. e., the avian “corticostriatal” projection system). Using retrograde and anterograde neuroanatomical pathway tracers to address this issue, we found that a large continuous expanse of the outer pallium projects to the striatum of the basal ganglia in pigeons. This expanse includes the Wulst and archistriatum as well as the entire outer rind of the pallium intervening between Wulst and archistriatum, termed by us the pallium externum (PE). In addition, the caudolateral neostriatum (NCL), pyriform cortex, and hippocampal complex also give rise to striatal projections in pigeon. A restricted number of these pallial regions (such as the “limbic” NCL, pyriform cortex, and ventral/caudal parts of the archistriatum) project to such ventral striatal structures as the olfactory tubercle (TO), nucleus accumbens (Ac), and bed nucleus of the stria terminalis (BNST). Such “limbic” pallial areas also project to medialmost LPO and lateralmost PA, while the hyperstriatum accessorium portion of the Wulst, the PE, and the dorsal parts of the archistriatum were found to project primarily to the remainder of LPO (the lateral two-thirds) and PA (the medial four-fifths). The available evidence indicates that the diverse pallial regions projecting to the striatum in birds, as in mammals, are parts of higher order sensory or motor systems. The extensive corticostriatal system in both birds and mammals appears to include two types of pallial neurons: (1) those that project to both striatum and brainstem (i. e., those in the Wulst and the archistriatum) and (2) those that project to striatum but not to brainstem (i. e., those in the PE). The lack of extensive corticostriatal projections from either type of neuron in anamniotes suggests that the anamniote-amniote evolutionary transition was marked by the emergence of the corticostriatal projection system as a prominent source of sensory and motor information for the striatum, possibly facilitating the role of the basal ganglia in movement control. © 1995 Wiley-Liss, Inc.     

Extensive co-occurrence of substance P and dynorphin in striatal projection neurons: an evolutionarily conserved feature of basal ganglia organization.

A number of different neuroactive substances have been found in striatal projection neurons and in fibers and terminals in their target areas, including substance P (SP), enkephalin (ENK), and dynorphin (DYN). In a preliminary report on birds and reptiles, we have suggested that SP and DYN are to a large extent found in the same striatal projection neurons and that ENK is found in a separate population of striatal projection neurons. In the present study, we have examined this issue in more detail in pigeons and turtles. Further, we have also explored this issue in rats to determine whether this is a phylogenetically conserved feature of basal ganglia organization. Simultaneous immunofluorescence double-labeling procedures were employed to explore the colocalization of SP and DYN, SP and ENK, and ENK and DYN in striatal neurons and in striatal, nigral, and pallidal fibers in pigeons, turtles, and rats. To guard against possible cross-reactivity of DYN and ENK antisera with each others' antigens, separate double-label studies were carried out with several different antisera that were specific for DYN peptides (e.g., dynorphin A 1-17, dynorphin B, leumorphin) or ENK peptides (leucine-enkephalin, metenkephalin-arg6-gly7-leu8, methionine-enkephalin-arg6-phe7). The results showed that SP and DYN co-occur extensively in specific populations of striatal projection neurons, whereas ENK typically is present in different populations of striatal projection neurons. In pigeons, 95-99% of all striatal neurons containing DYN were found to contain SP and vice versa. In contrast, only 1-3% of the SP+ striatal neurons and no DYN neurons contained ENK. Similarly, in turtles, greater than 75% of the SP+ neurons were DYN+ and vice versa, whereas ENK was observed in fewer than 5% of the SP+ neurons and 2% of the DYN+ neurons. Finally, in rats, more than 70% of the SP+ neurons contained DYN and vice versa, but ENK was found in only 5% of the SP+ neurons and in none of the DYN+ perikarya. Fiber double-labeling in the striatum and its target areas (the pallidum and substantia nigra) was also consonant with these observations in pigeons, turtles, and rats. These results, in conjunction with studies in cats by M.-J. Besson, A.M. Graybiel, and B. Quinn (1986; Soc Neurosci. Abs. 12:876) strongly indicate that the co-occurrence of SP and DYN in large numbers of striatonigral and striatopallidal projection neurons in a phylogenetically widespread, and therefore evolutionarily conserved, feature of basal ganglia organization.(ABSTRACT TRUNCATED AT 400 WORDS)     

Distribution of dopamine immunoreactivity in the forebrain and midbrain of the snake Python regius: a study with antibodies against dopamine

The distribution of dopamine (DA) immunoreactivity in the forebrain and midbrain of the ball python, Python regius, was studied by using recently developed antibodies against DA. In order to determine general and species-specific features of the DA system in reptiles, we have selected the ball python as a representative of a reptilian radiation that hitherto has not been the subject of (immuno)histochemical studies. Dopamine-containing cell bodies were found around the glomeruli and in the external plexiform layer of both the main and accessory olfactory bulb, but not in the telencephalon proper. In the diencephalon, DA cells were observed in several parts of the periventricular hypothalamic nucleus, in the periventricular organ, the ependymal wall of the infundibular recess, the lateral hypothalamic area, the magnocellular ventrolateral thalamic nucleus, and the pretectal posterodorsal nucleus. In the midbrain, DA cells were found in the ventral tegmental area, the substantia nigra, and the presumed reptilian homologue of the mammalian A8 cell group. Dopaminergic fibers and varicosities were observed throughout the whole brain, particularly in the telencephalon and diencephalon. The nucleus accumbens, striatum, olfactory tubercle, and nucleus of the accessory olfactory tract appear to have the most dense innervation, but the lateral septal nucleus, the dorsal ventricular ridge, and the nucleus sphericus also show numerous DA-containing fibers and varicosities. Except for the lateral cortex, cortical areas are not densely innervated by DA fibers. The DA system of the snake Python regius shares many features with that of lizards and turtles as determined with the same antibodies. The taxonomically close relationship between lizards and snakes, which together constitute the Squamata, is reflected in a similar distribution of DA fibers and varicosities to the dorsal ventricular ridge and the lateral cortex, and in the limited number of CSF-contacting DA neurons in the hypothalamus.     

Localization and characterization of angiotensin II receptor binding sites in the human basal ganglia, thalamus, midbrain pons, and cerebellum.

Angiotensin II (Ang II) binding sites were localized in the thalamus, basal ganglia, midbrain, and pons of the human central nervous system by in vitro autoradiography, employing 125I-[Sar1, Ile8]angiotensin II as the radioligand. High-density binding occurs in the substantia nigra pars compacta, the interpeduncular nucleus and two of the raphe nuclei, the raphe magnus, and median raphe nucleus. Moderate densities occur in the caudate nucleus, putamen, bed nucleus of the stria terminalis, rostral linear nucleus, caudal linear nucleus, dorsal and paramedian raphe nuclei, locus coeruleus, and region of the subcoeruleus, oral dorsal paramedian nucleus, and A5/periolivary region. Low levels occur in the region between the subthalamic nucleus and the zona incerta, the mediodorsal thalamic nucleus, the central gray, the lateral and medial parabrachial nuclei, and the molecular layer of the cerebellum. The high density of Ang II receptor binding in the substantia nigra occurs over pigmented, presumably dopaminergic, neurons. The binding in this site, and in the striatum, is not observed in any of the other species we have studied. It displays similar pharmacological characteristics to the Ang II receptor binding site in other regions of the human brain. Overall we demonstrate a discrete pattern of Ang II receptor binding sites in the human brain, which shows a high correlation with the distribution observed in other mammalian species.     

Cholinergic systems in the rat brain: III. Projections from the pontomesencephalic tegmentum to the thalamus, tectum, basal ganglia, and basal forebrain

The ascending cholinergic projections of the pedunculopontine and dorsolateral tegmental nuclei, referred to collectively as the pontomesencephalotegmental (PMT) cholinergic complex, were investigated by use of fluorescent tracer histology in combination with choline-O-acetyltransferase (ChAT) immunohistochemistry and acetylcholinesterase (AChE) pharmacohistochemistry. Propidium iodide, true blue, or Evans blue was infused into the anterior, reticular, mediodorsal, central medial, and posterior nuclear areas of the thalamus; the habenula; lateral geniculate; superior colliculus; pretectal/parafascicular area; subthalamic nucleus; caudate-putamen complex; globus pallidus; entopeduncular nucleus; substantia nigra; medial septal nucleus/vertical limb of the diagonal band area; magnocellular preoptic/ventral pallidal area; and lateral hypothalamus. In some animals, separate injections of propidium iodide and true blue were made into two different regions in the same rat brain, usually a dorsal and a ventral target, in order to assess collateralization patterns. Retrogradely transported fluorescent labels and ChAT and/or AChE were analyzed microscopically on the same brain section. All of the above-delimited targets were found to receive cholinergic input from the PMT cholinergic complex, but some regions were preferentially innervated by either the pedunculopontine or dorsolateral tegmental nucleus. The former subdivision of the PMT cholinergic complex projected selectively to extrapyramidal structures and the superior colliculus, whereas the dorsolateral tegmental nucleus was observed to provide cholinergic input preferentially to anterior thalamic regions and rostral portions of the basal forebrain. The PMT cholinergic neurons showed a tendency to collateralize extensively.     

The distribution of dopamine immunoreactivity in the forebrain and midbrain of the lizard Gekko gecko: an immunohistochemical study with antibodies against dopamine

The distribution of dopamine (DA) immunoreactivity in the forebrain and the midbrain of the lizard Gekko gecko was studied by using recently developed antibodies against DA. Dopamine-containing cells were found around the glomeruli of the olfactory bulb, in several parts of the periventricular hypothalamic nucleus, in the periventricular organ, the ependymal wall of the infundibular recess, the lateral hypothalamic area and the pretectal posterodorsal nucleus of the diencephalon, and in the ventral tegmental area, the substantia nigra, and the presumed reptilian equivalent of the mammalian A8 cell group of the mesencephalon. Dopaminergic fibers and terminals were observed throughout the whole brain, but particularly in the diencephalon and the telencephalon. The nucleus accumbens appears to have the most dense innervation, but also the striatum, amygdaloid complex, olfactory tubercle, septum, and dorsal ventricular ridge (especially its superficial zone) show numerous DA-containing fibers and terminals. Except for the lateral cortex, cortical areas are not densely innervated by DA fibers. In several respects DA distribution in the gekkonid brain differs from that in other reptiles studied. For instance, in the Gekko the dorsal ventricular ridge is densely innervated by DA fibers, whereas in turtles and crocodiles the same structure shows only weak catecholaminergic histofluorescence. When compared to the distribution of DA immunoreactivity in mammals, it appears that the DA system in the gekkonid telencephalon resembles the distribution of DA in the limbic forebrain and striatum of mammals. Whether these similarities in distribution of DA also imply similarities in function will be discussed.     

Reductions in N-acetylaspartylglutamate and the 67 kDa form of glutamic acid decarboxylase immunoreactivities in the visual system of albino and pigmented rats after optic nerve transections

This study compares the immunohistochemical distributions of N-acetylaspartylglutamate (NAAG) and the large isoform of the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase (GAD(67)) in the visual system of albino and pigmented rats. Most retinal ganglion cells and their axons were strongly immunoreactive for NAAG, whereas GAD(67) immunoreactivity was very sparse in these cells and projections. In retinorecipient zones, NAAG and GAD(67) immunoreactivities occurred in distinct populations of neurons and in dense networks of strongly immunoreactive fibers and synapses. Dual-labeling immunohistochemistry indicated that principal neurons were stained for NAAG, whereas local interneurons were stained for GAD(67). In contrast to the distribution observed in retinorecipient zones, most or all neurons were doubly stained for NAAG and GAD(67) in the thalamic reticular nucleus. Ten days after unilateral optic nerve transection, NAAG-immunoreactive fibers and synapses were substantially reduced in all contralateral retinal terminal zones. The posttransection pattern of NAAG-immunoreactive synaptic loss demarcated the contralateral and ipsilateral divisions of the retinal projections. In addition, an apparent transynaptic reduction in GAD(67) immunoreactivity was observed in some deafferented areas, such as the lateral geniculate. These findings suggest a complicated picture in which NAAG and GABA are segregated in distinct neuronal populations in primary visual targets, yet they are colocalized in neurons of the thalamic reticular nucleus. This is consistent with NAAG acting as a neurotransmitter release modulator that is coreleased with a variety of classical transmitters in specific neural pathways.     

The distribution of glutamic acid decarboxylase immunoreactivity in the diencephalon of the opossum and rabbit

We have examined the distribution of neurons and terminals immunoreactive for glutamic acid decarboxylase (GAD) in the thalamus and adjacent structures of the opossum (Didelphis virginiana) and the rabbit and have compared this distribution with the distributions we described previously for the cat and bushbaby (Galago senegalensis). The significance of these experiments depends, first, on the fact that GAD is the synthetic enzyme for GABA, and therefore that GAD immunoreactivity is a marker for GABAergic inhibitory neurons, and second, on previous findings that suggest that GABAergic neurons in the dorsal thalamus are local circuit neurons. In both cat and Galago, GAD-immunoreactive neurons are distributed essentially throughout the entire thalamus. In the opossum, GAD neurons are chiefly confined to the dorsal lateral geniculate nucleus and the lateral extremity of the lateral posterior nucleus. The distribution of GAD neurons in the rabbit is intermediate between that found in the opossum on the one hand and cat and Galago on the other. Like opossum, about 25% of the neurons in the lateral geniculate nucleus of rabbit are GAD immunoreactive. Unlike opossum, however, as many as 18% of the cells in the ventral posterior nucleus of the rabbit are GAD immunoreactive, and scattered cells are also labeled in other thalamic areas, such as the medial geniculate and the lateral group. Aside from the findings in the dorsal thalamus, the chief observation is that GAD-immunoreactive neurons and/or terminals densely fill all principal targets of the optic tract, including the ventral lateral geniculate nucleus; the superficial gray layer of the superior colliculus; the anterior, posterior, and olivary pretectal nuclei; the nucleus of the optic tract; and the medial and lateral terminal nuclei of the accessory optic tract. These results support the idea first put forward by Cajal that local circuit neurons increase in number during the course of the evolution of complex mammalian brains. If we can assume that the conservative opossum retains characteristics reflecting an early stage of mammalian evolution, the results suggest that thalamic local circuit neurons arose first in the visual system and only later in evolution spread throughout the thalamus.     

GABAergic neurons and axon terminals in the brainstem auditory nuclei of the gerbil

The anatomical localization of glutamic acid decarboxylase (GAD), the synthesizing enzyme for GABA, was analyzed in the brainstem auditory nuclei of the adult gerbil. GAD-positive terminals and somata were present in the cochlear nucleus, superior olivary complex, lateral lemniscus, and inferior colliculus in varying concentrations and patterns. One of the highest densities of GAD-positive terminals is found in the superficial layers of the dorsal cochlear nucleus (DCN), whereas the ventral cochlear nucleus (VCN) has somewhat fewer terminals that are arranged in pericellular plexuses. GAD-positive neurons occur mainly in the superficial and fusiform layers of the DCN and are scattered throughout the VCN. Within the superior olivary complex, the highest concentration of immunoreactive terminals and neurons occurs in the ventral and lateral nuclei of the trapezoid body. In contrast, the medial nucleus of the trapezoid body and the medial superior olive contain fewer GAD-positive puncta and probably no immunoreactive somata. The lateral superior olive and superior periolivary nucleus contain a few immunoreactive puncta but a large number of immunoreactive somata. In the midbrain, the nuclei of the lateral lemniscus contain a moderate number of GAD-positive puncta and a large number of different types of GAD-positive neurons. The inferior colliculus also contains a heterogeneous population of labeled somata, most of which are multipolar neurons. In addition, a high concentration of immunoreactive puncta occurs in this region. These data demonstrate a diverse distribution of GAD-positive neurons and puncta throughout the brainstem auditory nuclei and suggest that GABA might be an important neurotransmitter in the processing of auditory information.     

The roles of the cerebellum and basal ganglia in timing and error prediction

Recent evidence that the cerebellum and the basal ganglia are activated during the performance of cognitive and attention tasks challenges the prevailing view of their primary function in motor control. The specific roles of the basal ganglia and the cerebellum in cognition, however, have been difficult to identify. At least three functional hypotheses regarding their roles have been proposed. The first hypothesis suggests that their main function is to switch attentional set. The second hypothesis states that they provide error signals regarding stimuli or rewards. The third hypothesis is that they operate as an internal timing system, providing a precise representation of temporal information. Using functional magnetic resonance imaging, we tested these three hypotheses using a task-switching experiment with a 2 x 2 factorial design varying timing (random relative to fixed) and task order (unpredictable relative to predictable). This design allowed us to test whether switching between tasks, timing irregularity and/or task order unpredictability activate the basal ganglia and/or the cerebellum. We show that the cerebellum is primarily activated with timing irregularity while the anterior striatum is activated with task order unpredictability, supporting their distinctive roles in two forms of readjustment. Task order unpredictability alone, independent of reward delivery, is sufficient to induce striatal activation. In addition, activation of the cerebellum and basal ganglia were not specific to switching attention because these regions were both activated during switching between tasks and during the simultaneous maintenance of two tasks without switching between them.     

Dopaminergic regulation of glutamic acid decarboxylase mRNA expression and GABA release in the striatum: A review

Lindefors Nils: Dopaminergic Regulation of Glutamic Acid Decarboxylase mRNA Expression and GABA Release In the Striatum: A Minireview. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1993, 17(6): 887–903.

1. 1. The majority of neurons in the striatum (caudate-putamen, dorsal striatum; nucleus accumbens, ventral striatum) and in striatal projection regions (the pallidum, the entopeduncular nucleus and substantia nigra reticulata) use γ-aminobuturic acid (GABA) as transmitter and express glutamic acid decarboxylase (GAD; rate limiting enzyme) in the synthesis of GABA. GABA is the major inhibitory transmitter in the mammlian brain.

2. 2. GAD in brain is present as two isoenzymes, GAD₆₅ and GAD₆₇. GAD₆₅ is largely present as an inactive apoenzyme, which can be induced by nerve activity, while most GAD₆₇ is present as a pyridoxal phosphate-bound permanently active holoenzyme. Thus GAD₆₅ and GAD₆₇ seem to provide a dual system for the control of neuronal GABA synthesis.

3. 3. GAD mRNA expression can be visualised and quantified using in situ hybridisation, and GABA release can be quantified using in vivo microdialysis.

4. 4. Different populations of GABA neurons can be distinguished in both dorsal and ventral striatum as well as in other parts of the basal ganglia.

5. 5. Inhibition of dopaminergic transmission in the striatum by lesion of dopamine neurons or by neuroleptic treatment is followed by an increased release of GABA and increased expression of GAD₆₇ mRNA in a subpopulation of striatal medium-sized neurons which project to the globus pallidus, and increased striatal GAD enzyme activity.

6. 6. Increased dopaminergic transmission by repeated but not single doses of amphetamine is followed by decreased striatal GABA release and decreased GAD₆₇ mRNA expression in a subpopulation of medium-sized neurons in the striatum.

7. 7. Two populations of medium-sized GABA neurons in the striatum seem to be under tonic dopaminergic influence. The majority of these GABA neurons are under inhibitory influence, whereas a small number seem to be stimulated by dopamine.

8. 8. Specific changes in activity in subpopulations of striatal GABA neurons probably mediate the dopamine-dependent hypokinetic syndrome seen in Parkinson's disease and following neuroleptic treatment.

Collateral sprouting in central mesolimbic dopamine neurons: Biochemical and immunocytochemical evidence of changes in the activity and distribution of tyrosine hydroxylase in terminal fields and in cell bodies of A10 neurons

The olfactory tubercle of adult rats was examined for the development of collateral sprouts from intrinsic dopaminergic axons following unilateral olfactory bulbectomy. In the ipsilateral tubercle tyrosine hydroxylase (TH) activity began to increase by 10–14 days following the lesion, gradually reaching a maximum of 125% of control (P < 0.005) by 21 days where it remained permanently elevated. The rise of TH activity in the tubercle reflected changes of the dopaminergic innervation, since dopamine-β-hydroxylase (DBH) activity was unchanged, and lesions of the dorsal noradrenergic bundle reduced DBH but not TH activity in the tubercle. By immunocytochemical staining the elevation of TH reflected an increased number and altered distribution of TH-containing processes within the olfactory tubercle. By 30 days the uptake of [³H]dopamine into synaptosomes of the olfactory tubercle was also increased to 140% of control (P < 0.05). In the dopaminergic cell bodies of the ipsilateral A10 group (which innervate the tubercle) TH activity was transiently elevated to 121% (P < 0.05) by 4 days, returning to control levels by 10 days. Histologically no change in activity was detected. The results indicate that mesolimbic dopaminergic neurons of A10 which innervate the olfactory tubercle will sprout in response to removal of a major non-dopaminergic input, that the new innervation is sustained, and that during collateral sprouting there is a transient elevation of TH activity in the uninjured cell bodies which precedes the period of axonal growth. The findings suggest that (a) the increase of TH activity in the A10 cell bodies during collateral sprouting may be a reflection of an increase in the amount of enzyme protein required for transport into the enlarging terminal fields, (b) that as in development sprouts are in place before they reach biochemical maturity, (c) the biochemical mechanisms underlying collateral sprouting of uninjured neurons are not necessarily the same as those associated with regenerative sprouting in response to axonal injury, and (d) the development and the acquisition of biochemical maturation of collateral sprouts in the CNS involves complex two-way signalling between terminal field and cell bodies. The development of collateral sprouts of dopaminergic neurons may be the cellular substrate of the development of behavioral hyperactivity and aggression produced by bilateral olfactory bulbectomy in rat.     

Distribution of mu, delta, and kappa opiate receptor types in the forebrain and midbrain of pigeons

Ligands that are highly specific for the mu, delta, and kappa opiate receptor binding sites in mammalian brains have been identified and used to map the distribution of these receptor types in the brains of various mammalian species. In the present study, the selectivity and binding characteristics in the pigeon brain of three such ligands were examined by in vitro receptor binding techniques and found to be similar to those reported in previous studies on mammalian species. These ligands were then used in conjunction with autoradiographic receptor binding techniques to study the distribution of mu, delta, and kappa opiate receptor binding sites in the forebrain and midbrain of pigeons. The autoradiographic results indicated that the three opiate receptor types showed similar but not identical distributions. For example, mu, delta, and kappa receptors were all abundant within several parts of the cortical-equivalent region of the telencephalon, particularly the hyperstriatum ventrale and the medial neostriatum. In contrast, in other parts of the cortical-equivalent region of the avian telencephalon, such as the dorsal archistriatum and caudal neostriatum, only kappa receptors appeared to be abundant. Within the basal ganglia, all three types of opiate receptors were abundant in the striatum and low in the pallidum. Within the diencephalon, kappa and delta binding was high in the dorsal and dorsomedial thalamic nuclei, but the levels of all three receptor types were generally low in the specific sensory relay nuclei of the thalamus. Kappa binding and delta binding were high, but mu was low in the hypothalamus. Within the midbrain, all three receptor types were abundant in both the superficial and deep tectal layers, in periventricular areas, and in the tegmental dopaminergic cell groups. In many cases, the distribution of opiate receptors in the pigeon forebrain generally showed considerable overlap with the distribution of opioid peptide-containing fiber systems (for example, in the striatal portion of the basal ganglia), but there were some clear examples of receptor-ligand mismatch. For example, although all three receptor types are very abundant in the hyperstriatum ventrale, opioid peptide-containing fibers are sparse in this region. Conversely, within the pallidal portion of the basal ganglia, opioid peptide-containing fibers are abundant, but the levels of opiate receptors appear to be considerably lower than would be expected. Thus, receptor-ligand mismatches are not restricted to the mammalian brain, since they are a prominent feature of the organization of the brain opiate systems in pigeons.(ABSTRACT TRUNCATED AT 400 WORDS)     

GABA-immunoreactive synaptic boutons in the rat basal forebrain: comparison of neurons that project to the neocortex with pallidosubthalamic neurons

Although the basal forebrain, including the globus pallidus, contains a high concentration of gamma-aminobutyric acid (GABA), it is not known whether all types of neuron in the globus pallidus receive GABAergic synaptic input. We have studied two types of neuron: typical pallidal neurons that project to the subthalamic nucleus and magnocellular neurons which are found in the medial and ventral borders of the globus and project to the sensorimotor cortex. The postembedding immunogold staining of endogenous GABA revealed many preterminal axons and synaptic boutons that contained GABA immunoreactivity. Neurons that projected to the neocortex were postsynaptic to some of the GABA-immunoreactive boutons, the majority of which formed symmetrical membrane specializations. From a series of random electron micrographs through the perikarya and proximal dendrites of such retrogradely labelled neurons the density of GABA-containing afferent synaptic boutons was estimated to be 0.58 GABA-containing boutons per 100 micron of neuronal membrane. The GABA-containing boutons accounted for 72% of the total afferent input in the proximal regions of the pallidocortical neurons examined. The pallidosubthalamic neurons received many more afferent boutons than did the cortically projecting neurons, a high proportion (80.4%) of which were immunoreactive for GABA. The density of GABA-containing boutons in contact with pallidosubthalamic neurons was 8.9 boutons per 100 micron. It is concluded that cortically projecting basal forebrain neurons, that are probably cholinergic, are innervated by GABA-containing afferent boutons. However, pallidosubthalamic neurons in the same part of the basal forebrain are much more densely innervated by GABA-containing boutons.