Relationship between the corticostriatal terminals from areas 9 and 46, and those from area 8A, dorsal and rostral premotor cortex and area 24c: an anatomical substrate for cognition to action

Our previous data indicate that there are specific features of the corticostriatal pathways from the prefrontal cortex. First, corticostriatal pathways are composed of focal, circumscribed projections and of diffuse, widespread projections. Second, there is some convergence between terminal fields from different functional regions of the prefrontal cortex. Third, anterior cingulate projections from area 24b occupy a large region of the rostral striatum. The goal of this study was to determine whether these features are also common to the corticostriatal projections from area 8A (including the frontal eye field; FEF), the supplementary eye field (SEF), dorsal and rostral premotor cortex (PMdr) and area 24c. Using a new approach of three-dimensional reconstruction of the corticostriatal pathways, along with dual cortical tracer injections, we mapped the corticostriatal terminal fields from areas 9 and 46, 8A-FEF, SEF, PMdr and 24b and c. In addition, we placed injections of retrogradely transported tracers into key striatal regions. The results demonstrated that: (i) a diffuse projection system is a common feature of the corticostriatal projections from different frontal regions; (ii) key striatal regions receive convergent projections from areas 9 and 46 and from areas 8A-FEF, SEF, PMdr and 24c, suggesting a potential pivotal role of these striatal regions in integrating cortical information; (iii) projections from area 24c, like those from area 24b, terminate widely throughout the striatum, interfacing with terminals from several frontal areas. These features of the corticostriatal frontal pathways suggest a potential integrative striatal network for learning.     

Regulation of the polysialylated form of the neural cell adhesion molecule in the developing striatum: Effects of cortical lesions

Early in development, the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is expressed by growth cones, neuronal processes, and neuronal cell bodies. In rat striatum, PSA-NCAM expression becomes progressively restricted to pre- and postsynaptic membranes and is undetectable by postnatal day 25 (P25), i.e., after corticostriatal synaptogenesis. This study examined the effects of cortical lesions performed on P14, when the corticostriatal projection is already primarily unilateral and cortical inputs have not yet formed asymmetric synapses on striatal neurons. Rats were killed on P25, and PSA-NCAM expression was examined by immunoblotting and immunohistochemistry with light and electron microscopy. In contrast to the case in controls, PSA-NCAM expression was maintained in the striatum of lesioned pups. Ultrastructural studies showed that PSA-NCAM was present 1) in growth cone-like structures and neuronal processes and 2) in striatal neurons. Together with the presence of growth cones, the observation that the number of asymmetric synapses was unchanged in the denervated striatum suggests that axonal sprouting occurred in response to the lesion. This was confirmed by axonal labeling in the denervated striatum after injection of Fluoro-Ruby in the contralateral cortex. The data indicate that P14 cortical lesions affect PSA-NCAM expression in the developing striatum 1) by inducing a robust axonal plasticity resulting in the presence of immature presynaptic elements that contain PSA-NCAM and 2) by delaying the loss of PSA-NCAM expression in striatal neurons, suggesting that the lesion affects the time course of striatal maturation. J. Comp. Neurol. 389:289–308, 1997. © 1997 Wiley-Liss, Inc.     

Dopamine D2 receptors are present in prefrontal cortical afferents and their targets in patches of the rat caudate-putamen nucleus.

Glutamatergic neurons within the deep layers of the prefrontal cortex and dopaminergic neurons of the substantia nigra pars compacta preferentially terminate in patch-like regions within the caudate putamen nucleus (CPN). Activation of dopamine D2 receptors is known to potently modulate striatal glutamatergic transmission and may play a role in reward-based motor learning. To determine the cellular substrate for D2-mediated regulation of prefrontal corticostriatal transmission in striatal patches, we combined anterograde transport of biotinylated dextran amine (BDA) with immunogold-silver labeling of a D2 receptor antipeptide antiserum in rat brain. Injections centered in deep layers of the dorsal part of the anterior cingulate cortex, one of the prefrontal cortical regions, produced varicose axonal BDA labeling in a patch-like distribution in the dorsomedial CPN. Electron microscopy showed that in these patch compartments, BDA labeling was present exclusively in axons and terminals (total number = 581), 9% of which contained detectable D2-like immunoreactivity. Thirty percent of the BDA-labeled terminals formed asymmetric excitatory synapses with dendritic spine heads, and the remainder were without recognizable junctions. The recipient spines were unlabeled or contained immunogold-silver particles for D2 receptors. A few of the D2-labeled spines also received convergent, often nonsynaptic contact from D2-labeled terminals resembling dopaminergic afferents. In addition, the corticostriatal terminals often apposed spiny and nonspiny neuronal profiles that contained D2 labeling. These results suggest that dopamine D2 receptors are strategically positioned for presynaptic and postsynaptic modulation of prefrontal corticostriatal excitation of spiny neurons in striatal patches. The findings have direct implications for D2-mediated control of reward-related motor learning.     

Dysregulation of gene induction in corticostriatal circuits after repeated methylphenidate treatment in adolescent rats: differential effects on zif 268 and homer 1a

Psychostimulants and other dopamine agonists produce molecular changes in neurons of cortico-basal ganglia-cortical circuits, and such neuronal changes are implicated in behavioural disorders. Methylphenidate, a psychostimulant that causes dopamine overflow (among other effects), alters gene regulation in neurons of the striatum. The present study compared the effects of acute and repeated methylphenidate treatment on cortical and striatal gene regulation in adolescent rats. Changes in the expression of the immediate-early genes zif 268 and homer 1a were mapped in 23 striatal sectors and 22 cortical areas that provide input to these striatal sectors, in order to determine whether specific corticostriatal circuits were affected by these treatments. Acute administration of methylphenidate (5 mg/kg, i.p.) produced modest zif 268 induction in cortical areas. These cortical zif 268 responses were correlated in magnitude with zif 268 induction in functionally related striatal sectors. In contrast, after repeated methylphenidate treatment (10 mg/kg, 7 days), cortical and striatal gene induction were dissociated. In these animals, the methylphenidate challenge (5 mg/kg) produced significantly greater gene induction (zif 268 and homer 1a) in the cortex. This enhanced response was widespread but regionally selective, as it occurred predominantly in premotor, motor and somatosensory cortical areas. At the same time, striatal gene induction was partly suppressed (zif 268) or unchanged (homer 1a). Thus, repeated methylphenidate treatment disrupted the normally coordinated gene activation patterns in cortical and striatal nodes of corticostriatal circuits. This drug-induced dissociation in cortical and striatal functioning was associated with enhanced levels of behavioural stereotypies, suggesting disrupted motor switching function.     

Reduced corticostriatal functional connectivity in temporomandibular disorders

Although temporomandibular disorders (TMD) have been associated with abnormal gray matter volumes in cortical areas and in the striatum, the corticostriatal functional connectivity (FC) of patients with TMD has not been studied. Here, we studied 30 patients with TMD and 20 healthy controls that underwent clinical evaluations, including Helkimo indices, pain assessments, and resting‐state functional magnetic resonance imaging scans. The FCs of the striatal regions with the other brain areas were examined with a seed‐based approach. As seeds, we used the dorsal caudate, ventral caudate/nucleus accumbens, dorsal caudal putamen, and ventral rostral putamen regions. Voxel‐wise comparisons with controls revealed that the patients with TMD exhibited reduced FCs in the ventral corticostriatal circuitry, between the ventral striatum and ventral frontal cortices, including the anterior cingulate cortex and anterior insula; in the dorsal corticostriatal circuitry, between the dorsal striatum and the dorsal cortices, including the precentral gyrus and supramarginal gyrus; and also within the striatum. Additionally, we explored correlations between the reduced corticostriatal FCs and clinical measurements. These results directly supported the hypothesis that TMD is associated with reduced FCs in brain corticostriatal networks and that these reduced FCs may underlie the deficits in motor control, pain processing, and cognition in TMD. Our findings may contribute to the understanding of the etiologies and pathologies of TMD.     

From Progenitors to Progeny: Shaping Striatal Circuit Development and Function

Understanding how neurons of the striatum are formed and integrate into complex synaptic circuits is essential to provide insight into striatal function in health and disease. In this review, we summarize our current understanding of the development of striatal neurons and associated circuits with a focus on their embryonic origin. Specifically, we address the role of distinct types of embryonic progenitors, found in the proliferative zones of the ganglionic eminences in the ventral telencephalon, in the generation of diverse striatal interneurons and projection neurons. Indeed, recent evidence would suggest that embryonic progenitor origin dictates key characteristics of postnatal cells, including their neurochemical content, their location within striatum, and their long-range synaptic inputs. We also integrate recent observations regarding embryonic progenitors in cortical and other regions and discuss how this might inform future research on the ganglionic eminences. Last, we examine how embryonic progenitor dysfunction can alter striatal formation, as exemplified in Huntington''s disease and autism spectrum disorder, and how increased understanding of embryonic progenitors can have significant implications for future research directions and the development of improved therapeutic options.SIGNIFICANCE STATEMENT This review highlights recently defined novel roles for embryonic progenitor cells in shaping the functional properties of both projection neurons and interneurons of the striatum. It outlines the developmental mechanisms that guide neuronal development from progenitors in the embryonic ganglionic eminences to progeny in the striatum. Where questions remain open, we integrate observations from cortex and other regions to present possible avenues for future research. Last, we provide a progenitor-centric perspective onto both Huntington''s disease and autism spectrum disorder. We suggest that future investigations and manipulations of embryonic progenitor cells in both research and clinical settings will likely require careful consideration of their great intrinsic diversity and neurogenic potential.     

Altered Striatal Functional Connectivity in Subjects With an At-Risk Mental State for Psychosis

Recent functional imaging work in individuals experiencing an at-risk mental state (ARMS) for psychosis has implicated dorsal striatal abnormalities in the emergence of psychotic symptoms, contrasting with earlier findings implicating the ventral striatum. Our aims here were to characterize putative dorsal and ventral striatal circuit-level abnormalities in ARMS individuals using resting-state functional magnetic resonance imaging (fMRI) and to investigate their relationship to positive psychotic symptoms. Resting-state fMRI was acquired in 74 ARMS subjects and 35 matched healthy controls. An established method for mapping ventral and dorsal striatal functional connectivity was used to examine corticostriatal functional integrity. Positive psychotic symptoms were assessed using the Comprehensive Assessment of At-Risk Mental State and the Positive and Negative Syndrome Scale. Compared with healthy controls, ARMS subjects showed reductions in functional connectivity between the dorsal caudate and right dorsolateral prefrontal cortex, left rostral medial prefrontal cortex, and thalamus, and between the dorsal putamen and left thalamic and lenticular nuclei. ARMS subjects also showed increased functional connectivity between the ventral putamen and the insula, frontal operculum, and superior temporal gyrus bilaterally. No differences in ventral striatal (ie, nucleus accumbens) functional connectivity were found. Altered functional connectivity in corticostriatal circuits were significantly correlated with positive psychotic symptoms. Together, these results suggest that risk for psychosis is mediated by a complex interplay of alterations in both dorsal and ventral corticostriatal systems.Key words: ARMS, fMRI, resting state, striatum     

Dopamine, acetylcholine and nitric oxide systems interact to induce corticostriatal synaptic plasticity

Two distinct forms of synaptic plasticity have been described at corticostriatal synapses: long-term depression (LTD) and long-term potentiation (LTP). Both these enduring changes in the efficacy of excitatory neurotransmission in the striatum have a major impact on the physiological activity of the basal ganglia and are triggered by the stimulation of complex and independent cascades of intracellular second messenger systems. Along with the massive glutamatergic inputs originating from the cortex, striatal neurons receive a myriad of other synaptic contacts arising from different sources. In particular, while the nigrostriatal pathway provides this brain area with dopamine (DA), intrinsic circuits are the main source of acetylcholine (ACh) and nitric oxide (NO). The three neurotransmitter systems interact with each other to determine whether corticostriatal LTP or LTD is triggered in response to repetitive synaptic stimulation. Two distinct subtypes of striatal interneurons produce ACh and NO in the striatum. These interneurons are activated by the cortex during the induction phase of striatal plasticity, and stimulate, in turn, the intracellular changes in projection neurons required for LTD or LTP. Interneurons, therefore, exert a feedforward control of the excitability of striatal projection neurons by ensuring the coordinate expression of two alternative forms of synaptic plasticity at the same type of excitatory synapse. The integrative action exerted by striatal projection neurons on the converging information arising from the cortex, nigral DA neurons, and from ACh- and NO-producing interneurons dictates the final output of the striatum to the other structures of the basal ganglia.     

The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia.

BACKGROUND: Pathology of dorsolateral prefrontal cortex and dysregulation of dopaminergic neurons have been associated with the pathophysiology of schizophrenia, but how these phenomena relate to each other in patients has not been known. It has been hypothesized that prefrontal cortical pathology might induce both diminished steady-state and exaggerated responses of dopaminergic neurons to certain stimuli (e.g., stress). We examined the relationship between a measure of prefrontal neuronal pathology and striatal dopamine activity in patients with schizophrenia and in a nonhuman primate model of abnormal prefrontal cortical development. METHODS: In the patients, we studied in vivo markers of cortical neuronal pathology with NMR spectroscopic imaging and of steady-state striatal dopamine activity with radioreceptor imaging. In the monkeys, we used the same NMR technique and in vivo microdialysis. RESULTS: Measures of N-acetyl-aspartate concentrations (NAA) in dorsolateral prefrontal cortex strongly and selectively predicted D2 receptor availability in the striatum (n = 14, rho = -.64, p < .01), suggesting that the greater the apparent dorsolateral prefrontal cortex pathology, the less the steady-state dopamine activity in these patients. A similar relationship between NAA measures in dorsolateral prefrontal cortex and steady-state dopamine concentrations in the striatum was found in the monkeys (n = 5, rho = .70, p < .05). We then tested in the same monkeys the relationship of prefrontal NAA and striatal dopamine overflow following amphetamine infusion into dorsolateral prefrontal cortex. Under these conditions, the relationship was inverted, i.e., the greater the apparent dorsolateral prefrontal cortex pathology, the greater the dopamine release. CONCLUSIONS: These data demonstrate direct relationships between putative neuronal pathology in dorsolateral prefrontal cortex and striatal dopamine activity in human and nonhuman primates and implicate a mechanism for dopamine dysregulation in schizophrenia.     

Laminar Origin of Corticostriatal Projections to the Motor Putamen in the Macaque Brain

In the macaque brain, projections from distant, interconnected cortical areas converge in specific zones of the striatum. For example, specific zones of the motor putamen are targets of projections from frontal motor, inferior parietal, and ventrolateral prefrontal hand-related areas and thus are integral part of the so-called “lateral grasping network.” In the present study, we analyzed the laminar distribution of corticostriatal neurons projecting to different parts of the motor putamen. Retrograde neural tracers were injected in different parts of the putamen in 3 Macaca mulatta (one male) and the laminar distribution of the labeled corticostriatal neurons was analyzed quantitatively. In frontal motor areas and frontal operculum, where most labeled cells were located, almost everywhere the proportion of corticostriatal labeled neurons in layers III and/or VI was comparable or even stronger than in layer V. Furthermore, within these regions, the laminar distribution pattern of corticostriatal labeled neurons largely varied independently from their density and from the projecting area/sector, but likely according to the target striatal zone. Accordingly, the present data show that cortical areas may project in different ways to different striatal zones, which can be targets of specific combinations of signals originating from the various cortical layers of the areas of a given network. These observations extend current models of corticostriatal interactions, suggesting more complex modes of information processing in the basal ganglia for different motor and nonmotor functions and opening new questions on the architecture of the corticostriatal circuitry.SIGNIFICANCE STATEMENT Projections from the ipsilateral cerebral cortex are the major source of input to the striatum. Previous studies have provided evidence for distinct zones of the putamen specified by converging projections from specific sets of interconnected cortical areas. The present study shows that the distribution of corticostriatal neurons in the various layers of the primary motor and premotor areas varies depending on the target striatal zone. Accordingly, different striatal zones collect specific combinations of signals from the various cortical layers of their input areas, possibly differing in terms of coding, timing, and direction of information flow (e.g., feed-forward, or feed-back).     

Acetylcholine–Dopamine Interactions in the Pathophysiology and Treatment of CNS Disorders

Dopaminergic neurons in the substantia nigra pars compacta and ventral tegmental area of the midbrain form the nigrostriatal and mesocorticolimbic dopaminergic pathways that, respectively, project to dorsal and ventral striatum (including prefrontal cortex). These midbrain dopaminergic nuclei and their respective forebrain and cortical target areas are well established as serving a critical role in mediating voluntary motor control, as evidenced in Parkinson's disease, and incentive‐motivated behaviors and cognitive functions, as exhibited in drug addiction and schizophrenia, respectively. Although it cannot be disputed that excitatory and inhibitory amino acid‐based neurotransmitters, such as glutamate and GABA, play a vital role in modulating activity of midbrain dopaminergic neurons, recent evidence suggests that acetylcholine may be as important in regulating dopaminergic transmission. Midbrain dopaminergic cell tonic and phasic activity is closely dependent upon projections from hindbrain pedunculopontine and the laterodorsal tegmental nuclei, which comprises the only known cholinergic inputs to these neurons. In close coordination with glutamatergic and GABAergic activity, these excitatory cholinergic projections activate nicotinic and muscarinic acetylcholine receptors within the substantia nigra and ventral tegmental area to modulate dopamine transmission in the dorsal/ventral striatum and prefrontal cortex. Additionally, acetylcholine‐containing interneurons in the striatum also constitute an important neural substrate to provide further cholinergic modulation of forebrain striatal dopaminergic transmission. In this review, we examine neurological and psychopathological conditions associated with dysfunctions in the interaction of acetylcholine and dopamine and conventional and new pharmacological approaches to treat these disorders.     

Developmentally regulated and evolutionarily conserved expression of SLITRK1 in brain circuits implicated in Tourette syndrome

Tourette syndrome (TS) is an inherited developmental neuropsychiatric disorder characterized by vocal and motor tics. Multiple lines of neurophysiological evidence implicate dysfunction in the corticostriatal‐thalamocortical circuits in the etiology of TS. We recently identified rare sequence variants in the Slit and Trk‐like family member 1 (SLITRK1) gene associated with TS. SLITRK1, a single‐pass transmembrane protein, displays similarities to the SLIT family of secreted ligands, which have roles in axonal repulsion and dendritic patterning, but its function and developmental expression remain largely unknown. Here we provide evidence that SLITRK1 has a developmentally regulated expression pattern in projection neurons of the corticostriatal‐thalamocortical circuits. SLITRK1 is further enriched in the somatodendritic compartment and cytoplasmic vesicles of cortical pyramidal neurons in mouse, monkey, and human brain, observations suggestive of an evolutionarily conserved function in mammals. SLITRK1 is transiently expressed in the striosomal/patch compartment of the mammalian striatum and moreover is associated with the direct output pathway; adult striatal expression is confined to cholinergic interneurons. These analyses demonstrate that the expression of SLITRK1 is dynamic and specifically associated with the circuits most commonly implicated in TS and related disorders, suggesting that SLITRK1 contributes to the development of corticostriatal‐thalamocortical circuits. J. Comp. Neurol. 513:21–37, 2009. © 2008 Wiley‐Liss, Inc.     

Long-lasting dysregulation of gene expression in corticostriatal circuits after repeated cocaine treatment in adult rats: effects on zif 268 and homer 1a

Human imaging studies show that psychostimulants such as cocaine produce functional changes in several areas of cortex and striatum. These may reflect neuronal changes related to addiction. We employed gene markers ( zif 268 and homer 1a ) that offer a high anatomical resolution to map cocaine-induced changes in 22 cortical areas and 23 functionally related striatal sectors, in order to determine the corticostriatal circuits altered by repeated cocaine exposure (25 mg/kg, 5 days). Effects were investigated 1 day and 21 days after repeated treatment to assess their longevity. Repeated cocaine treatment increased basal expression of zif 268 predominantly in sensorimotor areas of the cortex. This effect endured for 3 weeks in some areas. These changes were accompanied by attenuated gene induction by a cocaine challenge. In the insular cortex, the cocaine challenge produced a decrease in zif 268 expression after the 21-day, but not 1-day, withdrawal period. In the striatum, cocaine also affected mostly sensorimotor sectors. Repeated cocaine resulted in blunted inducibility of both zif 268 and homer 1a , changes that were still very robust 3 weeks later. Thus, our findings demonstrate that cocaine produces robust and long-lasting changes in gene regulation predominantly in sensorimotor corticostriatal circuits. These neuronal changes were associated with behavioral stereotypies, which are thought to reflect dysfunction in sensorimotor corticostriatal circuits. Future studies will have to elucidate the role of such neuronal changes in psychostimulant addiction.     

3H]Dopamine release in striatum in response to cortical stimulation in a corticostriatal slice preparation

A new method has been developed to investigate corticostriatal glutamatergic influence on [3H]dopamine release in striatum in complex corticostriatal slice preparation in vitro. Horizontal slices containing the striatum and the adjacent prefrontal cortex of rat brain were cut in a plane that maintains corticostriatal connections. After incubation with [3H]dopamine, slices were submerged in a two-compartment bath so that the cortical region was contained entirely in one compartment, corpus callosum passed through a silicone greased slot, and the striatal region was contained in the other compartment. A cannula was placed just above the striatal part of the slice and effluent was collected with a peristaltic pump, released tritiated materials were counted with a liquid scintillation counter. Electric field stimulation of cortex increased the release of [3H]dopamine in the striatum. Bicuculline (1 mM) increased the basal and stimulated release of [3H]dopamine in the striatum in response to cortical stimulation of cortex indicating the GABAergic control on dopamine release. This method allows investigation of the effect of cortical stimulation on glutamate-dopamine-GABA interactions in the striatum in vitro that might help to understand better the neurochemical background of schizophrenia or Parkinson's disease.     

Cellular interactions in the striatum involving neuronal systems using "classical" neurotransmitters: possible functional implications.

The neostriatum contains a wide variety of neuroactive substances associated with several well-defined functional neuronal systems. This structure, which is the seat of numerous neurological pathological disorders, is commonly used as a model for studying the basic mechanisms of neurotransmitter interactions in the brain and their putative involvement in striatal functions. Increasing interest has been focusing lately on the cellular interactions that may occur between the corticostriatal putatively glutamatergic system and the nigrostriatal dopaminergic input. Current evidence suggests that the activatory corticostriatal glutamatergic input may play a more crucial role in regulating striatal functions than was formerly assumed in comparison with the dopaminergic input. The key role of cholinergic interneurons in the striatum may therefore be attributable to the fact that they modulate the glutamatergic transmission to GABA striatal efferent neurons. Likewise, dopamine may actually act indirectly in the striatum by "tuning down" the cortical excitation of striatal neurons. Consequently, an impairment of the dopaminergic transmission such as that occurring in Parkinsonism may lead to an increase in the corticostriatal glutamatergic transmission, which may further contribute towards reinforcing the "imbalance" between subsets of striatal neuronal systems controlling the output of the basal ganglia.     

Gray matter correlates of dopaminergic degeneration in Parkinson's disease: A hybrid PET/MR study using 18F‐FP‐CIT

Dopaminergic degeneration is a hallmark of Parkinson's disease (PD), which causes various symptoms affected by corticostriatal circuits. So far, the relationship between cortical changes and dopamine loss in the striatum is unclear. Here, we evaluate the gray matter (GM) changes in accordance with striatal dopaminergic degeneration in PD using hybrid PET/MR. Sixteen patients with idiopathic PD underwent ¹⁸F‐FP‐CIT PET/MR. To measure dopaminergic degeneration in PD, binding ratio (BR) of dopamine transporter in striatum was evaluated by ¹⁸F‐FP‐CIT. Voxel‐based morphometry (VBM) was used to evaluate GM density. We obtained voxelwise correlation maps of GM density according to the striatal BR. Voxel‐by‐voxel correlation between BR maps and GM density maps was done to evaluate region‐specific correlation of striatal dopaminergic degeneration. There was a trend of positive correlation between striatal BR and GM density in the cerebellum, parahippocampal gyri, and frontal cortex. A trend of negative correlation between striatal BR and GM density in the medial occipital cortex was found. Voxel‐by‐voxel correlation revealed that the positive correlation was mainly dependent on anterior striatal BR, while posterior striatal BR mostly showed negative correlation with GM density in occipital and temporal cortices. Decreased GM density related to anterior striatal dopaminergic degeneration might demonstrate degeneration of dopaminergic nonmotor circuits. Furthermore, the negative correlation could be related to the motor circuits of posterior striatum. Our integrated PET/MR study suggests that the widespread structural progressive changes in PD could denote the cortical functional correlates of the degeneration of striatal dopaminergic circuits. Hum Brain Mapp 37:1710–1721, 2016. © 2016 Wiley Periodicals, Inc .     

Pattern of corticostriatal innervation in organotypic cocultures is dependent on the age of the cortical tissue

The patch-matrix organization of the striatum is defined by the selective expression of neuronal markers and a semisegregated pattern of afferents and efferents that develops before birth in all mammals. Differential projections from 'limbic' and 'somatomotor' cortices contribute to the selective circuitry of patch ("striosome") and matrix compartments. Organotypic cultures were used to determine the pattern of early corticostriatal innervation as a first step toward understanding the role of cortical innervation in the development of striatal patch-matrix organization. Perinatal striatum (E19-P4) was cocultured with the cortex obtained from same-age or different-age rats in the presence or absence of substantia nigra obtained from E14-15 fetuses. After 4-21 days in vitro, crystals of biocytin were placed directly onto the cortical piece to trace cortical projections into the striatal piece. Cortex obtained from fetuses (E19-22) or neonatal (P0-1) rats gave rise to a dense innervation of both prenatal and postnatal striatal slices; however, the pattern of biocytin-labeled fibers was found to be highly dependent on the age of the cortical tissue used. Cortex derived from rats between E20 and P1 gave rise to a heterogeneous distribution of fibers indicative of striatal patches when combined with striatal slices from same-age or younger (E18-19) fetuses. Cortex from E18-19 fetuses produced a homogeneous innervation even when cocultured with older striatal tissue in which the striatal patches were already present. The postnatal cortex (P2-P5) gave rise to little to no innervation of striatum of all ages. Similar findings were obtained with the use of either prelimbic or somatosensory cortex. In double- and triple-labeled cultures, the distribution of corticostriatal fibers overlapped substantially with patches of developing striatal neurons, as revealed by DARPP-32 immunocytochemistry. Dopaminergic innervation present when the substantia nigra was included in the cocultures also distributed preferentially to the developing patch compartment, but it did not substantially alter the pattern of corticostriatal innervation. These findings suggest that the cortex provides directive signals to the developing striatum rather than simply responding to the presence of patches that have already formed.     

Electrically evoked turning: asymmetric and symmetric collision between anteromedial cortex and striatum

Electrical stimulation of the anteromedial cortex (AMC) or striatum of rats evoked contraversive eye, head and body movements. In these experiments we test which neurons and which pathways are responsible for the turning by delivering conditioning (C) pulses to one site and test (T) pulses to the second site, and measuring the frequency of pulse pairs required to evoke a full turn in 10 s. Decreases in the required frequency were usually found at C-T intervals from 0.6 to 1.0 ms, whether the C pulses were delivered to the AMC or to the striatum. This symmetric effect is attributed to collision in fast-conducting axons connecting cortex and striatum. Symmetric collision at C-T intervals of 2–4 ms was observed between cortex and 3 dorsal striatal sites, suggesting slower axons from cortex to these dorsal striatal sites. In several animals, asymmetric changes in required frequency also occurred. When the C pulses were presented via the striatal electrode, the recovery in required frequency occurred at C-T intervals of 1–4 ms, but when the C pulses were presented via the cortical electrode, recovery occurred at C-T intervals of 2–50 ms. This asymmetry is attributed to indirect (i.e., transynaptic) activation of corticostriatal or striatal output axons. These results suggest that in both cortex and striatum there are synapses, transmitting from rostral to caudal, which are important for electrically evoked turning. When C and T pulses were delivered to the same site, decreases in required frequency occurred at C-T intervals from 0.4 to 4 ms, attributable to recovery from refractoriness. In 3 striatal sites, however, large changes were also seen at C-T intervals from 6 to 50 ms. In all 3 sites, asymmetric collision occurred at these same intervals. The recovery at long C-T intervals could be due to transynaptic collision also, resulting from the simultaneous activation of presynaptic and postsynaptic axons by a single striatal electrode.     

Raclopride or high‐frequency stimulation of the subthalamic nucleus stops cocaine‐induced motor stereotypy and restores related alterations in prefrontal basal ganglia circuits

Motor stereotypy is a key symptom of various neurological or neuropsychiatric disorders. Neuroleptics or the promising treatment using deep brain stimulation stops stereotypies but the mechanisms underlying their actions are unclear. In rat, motor stereotypies are linked to an imbalance between prefrontal and sensorimotor cortico‐basal ganglia circuits. Indeed, cortico‐nigral transmission was reduced in the prefrontal but not sensorimotor basal ganglia circuits and dopamine and acetylcholine release was altered in the prefrontal but not sensorimotor territory of the dorsal striatum. Furthermore, cholinergic transmission in the prefrontal territory of the dorsal striatum plays a crucial role in the arrest of motor stereotypy. Here we found that, as previously observed for raclopride, high‐frequency stimulation of the subthalamic nucleus (HFS STN) rapidly stopped cocaine‐induced motor stereotypies in rat. Importantly, raclopride and HFS STN exerted a strong effect on cocaine‐induced alterations in prefrontal basal ganglia circuits. Raclopride restored the cholinergic transmission in the prefrontal territory of the dorsal striatum and the cortico‐nigral information transmissions in the prefrontal basal ganglia circuits. HFS STN also restored the N‐methyl‐d ‐aspartic‐acid‐evoked release of acetylcholine and dopamine in the prefrontal territory of the dorsal striatum. However, in contrast to raclopride, HFS STN did not restore the cortico‐substantia nigra pars reticulata transmissions but exerted strong inhibitory and excitatory effects on neuronal activity in the prefrontal subdivision of the substantia nigra pars reticulata. Thus, both raclopride and HFS STN stop cocaine‐induced motor stereotypy, but exert different effects on the related alterations in the prefrontal basal ganglia circuits.     

Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat.

The anterograde tracer Phaseolus vulgaris-leucoagglutinin was used to examine the topographical organization of the projections to the striatum arising from the various cytoarchitectonic subdivisions of the prefrontal cortex in the rat. The relationship of the prefrontal cortical fibres with the compartmental organization of the ventral striatum was assessed by combining PHA-L tracing and enkephalin-immunohistochemistry. The prefrontal cortex projects bilaterally with an ipsilateral predominance to the striatum, sparing only the lateral part of the caudate-putamen complex. Each of the cytoarchitectonic subfields of the prefrontal cortex has a longitudinally oriented striatal terminal field that overlaps slightly with those of adjacent prefrontal areas. The projections of the medial subdivision of the prefrontal cortex distribute to rostral and medial parts of the striatum, whereas the lateral prefrontal subdivision projects to more caudal and lateral striatal areas. The terminal fields of the orbital prefrontal areas involve midventral and ventromedial parts of the caudate-putamen complex. The projection of the ventral orbital area overlaps with that of the prelimbic area in the ventromedial part of the caudate-putamen. In the "shell" region of the nucleus accumbens, fibres arising from the prelimbic area concentrate in areas of high cell density that are weakly enkephalin-immunoreactive, whereas fibres from the infralimbic area avoid such areas. Rostrolaterally in the "core" region of the nucleus accumbens, fibres from deep layer V and layer VI of the dorsal part of the prelimbic area avoid the enkephalin-positive areas surrounding the anterior commissure and distribute in an inhomogeneous way over the intervening moderately enkephalin-immunoreactive compartment. The other prefrontal afferents show only a preference for, but are not restricted to, the latter compartment. In the border region between the nucleus accumbens and the ventromedial part of the caudate-putamen complex, patches of strong enkephalin immunoreactivity receive prefrontal cortical input from deep layer V and layer VI, whereas fibres from more superficial cortical layers project to the surrounding matrix. Individual cytoarchitectonic subfields of the prefrontal cortex thus have circumscribed terminal domains in the striatum. In combination with data on the organization of the midline and intralaminar thalamostriatal and thalamoprefrontal projections, the present results establish that the projections of the prefrontal cortical subfields converge in the striatum with those of their midline and intralaminar afferent nuclei. The present findings further demonstrate that the relationship of the prefrontal corticostriatal fibres with the neurochemical compartments of the ventral striatum can be influenced by both the areal and the laminar origin of the cortical afferents, depending on the particular ventral striatal region under consideration.