Vocal control pathways through the anterior forebrain of a parrot (Melopsittacus undulatus)

A feature of the telencephalic vocal control system in the budgerigar (Melopsittacus undulatus) that has been hypothesized to represent a profound difference in organization from the oscine vocal system is its reported lack of an inherent circuit through the anterior forebrain. The present study reports anatomical connections that indicate the existence of an anterior forebrain circuit comparable in important ways to the “recursive” pathway of oscine songbirds. Results from anterograde and retrograde tracing experiments with biocytin and fluorescently labeled dextran amines indicate that the central nucleus of the anterior archistriatum (AAc) is the source of ascending projections upon the oval nuclei of the anterior neostriatum and ventral hyperstriatum (NAo and HVo, respectively). Efferent projections from the latter nuclei terminate in the lateral neostriatum afferent to AAc, thereby forming a short recurrent pathway through the pallium. Previously reported projections from HVo and NAo upon the magnocellular nucleus of the lobus parolfactorius (LPOm), and from LPOm onto the magnocellular nucleus of the dorsal thalamus (DMm; G.F. Striedter [1994] J. Comp. Neurol. 343:35–56), are confirmed. A specific projection from DMm onto NAom is also demonstrated; therefore, a recurrent pathway through the basal forebrain also exists in the budgerigar vocal system that is similar to the anterior forebrain circuit of oscine songbirds. Parallels between these circuits and mammalian basal ganglia-thalamo-cortical circuits are discussed. It is hypothesized that vocal control nuclei of the avian anterior neostriatum may perform a function similar to the primate supplemental motor area. J. Comp. Neurol. 377:179–206, 1997. © 1997 Wiley-Liss, Inc.     

Homogeneous processing in the striatal direct and indirect pathways: single body part sensitive type IIb neurons may express either dopamine receptor D1 or D2

Striatal medium spiny projection neurons (MSNs) output through two diverging circuits, the ‘direct and indirect pathways’ which originate from minimally overlapping populations of MSNs expressing either the dopamine receptor D1 or the dopamine receptor D2. One modern theory of direct and indirect pathway function proposes that activation of direct pathway MSNs facilitates output of desired motor programs, while activation of indirect pathway MSNs inhibits competing motor programs. A separate theory suggests that coordinated timing or synchrony of the direct and indirect pathways is critical for the execution of refined movements. These hypotheses are made testable by a common type of striatal neuron known as type IIb MSNs. Clusters of these MSNs exhibit phasic increases in firing rate related to sensorimotor activity of single body parts. If these MSNs were to reside in only the direct pathway, evidence would be provided that D1 MSNs are ‘motor program’ specific, which would lend credence to the ‘competing motor programs’ hypothesis. However, if type IIb MSNs reside in both pathways, evidence would be provided for the ‘coordinated timing or synchrony’ hypothesis. Our results show that type IIb neurons may express either D1 or D2. This evidence supports the theory that the coordinated timing or synchrony of the direct and indirect pathways is critical for refined movements. We also propose a model in which the direct and indirect pathways act as a differentiator circuit, providing a possible mechanism by which coordinated activity of D1 and D2 neurons may output meaningful somatosensorimotor information to downstream structures.     

Phylotypic expression of the bHLH genes Neurogenin2, Neurod,and Mash1 in the mouse embryonic forebrain

In the anamniote model animals, zebrafish and Xenopus laevis, highly comparable early forebrain expression patterns of proneural basic helix‐loop‐helix (bHLH) genes relevant for neurogenesis (atonal homologs, i.e., neurogenins/NeuroD and achaete‐scute homologs, i.e., Ascl/ash) were previously revealed during a particular period of development (zebrafish: 3 days; frog: stage 48). Neurogenins/NeuroD on the one hand and Ascl1/ash1 on the other hand exhibit essentially mutually exclusive spatial patterns, probably reflecting different positional information received within the neural tube, and appear to underlie glutamatergic versus GABAergic neuronal differentiation, respectively. Significant data suggest that similar complementary localizations of these proneural genes and corresponding differentiation pathways also exist in the mouse, the prominent mammalian model. The present article reports on detailed mouse brain bHLH gene expression patterns to fill existing gaps in the identification of expression domains, especially outside the telencephalon. Clearly, there are strong similarities in the complementarity of territories expressing Ascl1/Mash 1 versus neurogenins/NeuroD in the entire mouse forebrain, except for the pretectal alar plate and basal plate of prosomeres 1–3. The analysis substantiates localization of neurogenins/NeuroD in the pallium, eminentia thalami, and dorsal thalamus, and expression of Ascl1/Mash 1 in the striatal and septal subpallium, preoptic region, ventral thalamus, and hypothalamus, which is highly similar to the situation described in Xenopus and zebrafish. Thus, all three vertebrate model species display a “phylotypic stage or period” corresponding to a temporally and spatially defined control of neurogenesis during forebrain development, ultimately resulting in the differentiation of distinct populations of glutamatergic versus GABAergic neurons. J. Comp. Neurol. 518:851–871, 2010. © 2009 Wiley‐Liss, Inc.     

Cannabidiol reduced the striatal atrophy caused 3-nitropropionic acid in vivo by mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors

The neuroprotective potential of cannabinoids has been examined in rats with striatal lesions caused by 3-nitropropionic acic (3NP), an inhibitor of mitochondrial complex II. We used the CB1 agonist arachidonyl-2-chloroethylamide (ACEA), the CB2 agonist HU-308, and cannabidiol (CBD), an antioxidant phytocannabinoid with negligible affinity for cannabinoid receptors. The administration of 3NP reduced GABA contents and also mRNA levels for several markers of striatal GABAergic projection neurons, including proenkephalin (PENK), substance P (SP) and neuronal-specific enolase (NSE). We also found reductions in mRNA levels for superoxide dismutase-1 (SOD-1) and -2 (SOD-2), which indicated that 3NP reduced the endogenous antioxidant defences. The administration of CBD, but not ACEA or HU-308, completely reversed 3NP-induced reductions in GABA contents and mRNA levels for SP, NSE and SOD-2, and partially attenuated those found in SOD-1 and PENK. This indicates that CBD is neuroprotective but acted preferentially on striatal neurons that project to the substantia nigra. The effects of CBD were not reversed by the CB1 receptor antagonist SR141716. The same happened with the TRPV1 receptor antagonist capsazepine, in concordance with the observation that capsaicin, a TRPV1 receptor agonist, failed to reproduce the CBD effects. The effects of CBD were also independent of adenosine signalling as they were not attenuated by the adenosine A2A receptor antagonist MSX-3. In summary, this study demonstrates that CBD provides neuroprotection against 3NP-induced striatal damage, which may be relevant for Huntington's disease, a disorder characterized by the preferential loss of striatal projection neurons. This capability seems to be based exclusively on the antioxidant properties of CBD.     

Exploring the role of striatal D1 and D2 medium spiny neurons in action selection using a virtual robotic framework

The basal ganglia have been hypothesized to be involved in action selection, i.e. resolving competition between simultaneously activated motor programs. It has been shown that the direct pathway facilitates action execution whereas the indirect pathway inhibits it. However, as the pathways are both active during an action, it remains unclear whether their role is co‐operative or competitive. In order to investigate this issue, we developed a striatal model consisting of D1 and D2 medium spiny neurons (MSNs) and interfaced it to a simulated robot moving in an environment. We demonstrate that this model is able to reproduce key behavioral features of several experiments involving optogenetic manipulation of the striatum, such as freezing and ambulation. We then investigate the interaction of D1‐ and D2‐MSNs. We find that their fundamental relationship is co‐operative within a channel and competitive between channels; this turns out to be crucial for action selection. However, individual pairs of D1‐ and D2‐MSNs may exhibit predominantly competition or co‐operation depending on their distance, and D1‐ and D2‐MSNs population activity can alternate between co‐operation and competition modes during a stimulation. Additionally, our results show that D2–D2 connectivity between channels is necessary for effective resolution of competition; in its absence, a conflict of two motor programs typically results in neither being selected.     

Differential regulation of the dopamine D1, D2 and D3 receptor gene expression and changes in the phenotype of the striatal neurons in mice lacking the dopamine transporter

Mice with a genetic disruption of the dopamine transporter (DAT-/-) exhibit locomotor hyperactivity and profound alterations in the homeostasis of the nigrostriatal system, e.g. a dramatic increase in the extracellular dopamine level. Here, we investigated the adaptive changes in dopamine D1, D2 and D3 receptor gene expression in the caudate putamen and nucleus accumbens of DAT-/- mice. We used quantitative in situ hybridization and found that the constitutive hyperdopaminergia results in opposite regulations in the gene expression for the dopamine receptors. In DAT-/- mice, we observed increased mRNA levels encoding the D3 receptor (caudate putamen, +60-85%; nucleus accumbens, +40-107%), and decreased mRNA levels for both D1 (caudate putamen, -34%; nucleus accumbens, -45%) and D2 receptors (caudate putamen, -36%; nucleus accumbens, -33%). Furthermore, we assessed the phenotypical organization of the striatal efferent neurons by using double in situ hybridization. Our results show that in DAT+/+ mice, D1 and D2 receptor mRNAs are segregated in two different main populations corresponding to substance P and preproenkephalin A mRNA-containing neurons, respectively. The phenotype of D1 or D2 mRNA-containing neurons was unchanged in both the caudate putamen and nucleus accumbens of DAT-/- mice. Interestingly, we found an increased density of preproenkephalin A-negative neurons that express the D3 receptor mRNA in the nucleus accumbens (core, +35%; shell, +46%) of DAT-/- mice. Our data further support the critical role for the D3 receptor in the regulation of D1-D2 interactions, an action being restricted to neurons coexpressing D1 and D3 receptors in the nucleus accumbens.     

Muscarinic m1 and m2 receptor proteins in local circuit and projection neurons of the primate striatum: anatomical evidence for cholinergic modulation of glutamatergic prefronto-striatal pathways

The cellular and subcellular localization of muscarinic receptor proteins m1 and m2 was examined in the neostriatum of macaque monkeys by using light and electron microscopic immunocytochemical techniques. Double-labeling immunocytochemistry revealed m1 receptors in calbindin-D28k--positive medium spiny projection neurons. Muscarinic m1 labeling was dramatically more intense in the striatal matrix compartment in juvenile monkeys but more intense in striosomes in the adult caudate, suggesting that m1 expression undergoes a developmental age-dependent change. Ultrastructurally, m1 receptors were predominantly localized in asymmetric synapse-forming spines, indicating that these spines receive extrastriatal excitatory afferents. The association of m1-positive spines with lesion-induced degenerating prefronto-striatal axon terminals demonstrated that these afferents originate in part from the prefrontal cortex. The synaptic localization of m1 in these spines indicates a role of m1 in the modulation of excitatory neurotransmission. To a lesser extent, m1 was present in symmetric synapses, where it may also modulate inhibitory neurotransmission originating from local striatal neurons or the substantia nigra. Conversely, m2/choline acetyltransferase (ChAT) double labeling revealed that m2-positive neurons corresponded to large aspiny cholinergic interneurons and ultrastructurally, that the majority of m2 labeled axons formed symmetric synapses. The remarkable segregation of the m1 and m2 receptor proteins to projection and local circuit neurons suggests a functional segregation of m1 and m2 mediated cholinergic actions in the striatum: m1 receptors modulate extrinsic glutamatergic and monoaminergic afferents and intrinsic GABAergic afferents onto projection neurons, whereas m2 receptors regulate acetylcholine release from axons of cholinergic interneurons.     

Resveratrol prevents CA1 neurons against ischemic injury by parallel modulation of both GSK‐3β and CREB through PI3‐K/Akt pathways

Accumulating evidence indicates that resveratrol potently protects against cerebral ischemia damage due to its oxygen free radicals scavenging and antioxidant properties. However, cellular mechanisms that may underlie the neuroprotective effects of resveratrol in brain ischemia are not fully understood yet. This study aimed to investigate the potential association between the neuroprotective effect of resveratrol and the apoptosis/survival signaling pathways, in particular the glycogen synthase kinase 3 (GSK‐3β) and cAMP response element‐binding protein (CREB) through phosphatidylinositol 3‐kinase (PI3‐K)‐dependent pathway. An experimental model of global cerebral ischemia was induced in rats by the four‐vessel occlusion method for 10 min and followed by different periods of reperfusion. Nissl staining indicated extensive neuronal death at 7 days after ischemia/reperfusion. Administration of resveratrol by i.p. injections (30 mg/kg) for 7 days before ischemia significantly attenuated neuronal death. Both GSK‐3β and CREB appear to play a critical role in resveratrol neuroprotection through the PI3‐K/Akt pathway, as resveratrol pretreatment increased the phosphorylation of Akt, GSK‐3β and CREB in 1 h in the CA1 hippocampus after ischemia/reperfusion. Furthermore, administration of LY294002, an inhibitor of PI3‐K, compromised the neuroprotective effect of resveratrol and decreased the level of p‐Akt, p‐GSK‐3β and p‐CREB after ischemic injury. Taken together, the results suggest that resveratrol protects against delayed neuronal death in the hippocampal CA1 by maintaining the pro‐survival states of Akt, GSK‐3β and CREB pathways. These data suggest that the neuroprotective effect of resveratrol may be mediated through activation of the PI3‐K/Akt signaling pathway, subsequently downregulating expression of GSK‐3β and CREB, thereby leading to prevention of neuronal death after brain ischemia in rats.