Striatal Field Research Articles

Histaminergic Control of Corticostriatal Synaptic Plasticity during Early Postnatal Development.

A reduction in the synthesis of the neuromodulator histamine has been associated with Tourette's syndrome and obsessive-compulsive disorder. Symptoms of these disorders are thought to arise from a dysfunction or aberrant development ofcorticostriatal circuits. Here, we investigated how histamine affects developing corticostriatal circuits, both acutely and longer-term, during the first postnatal weeks, using patch-clamp and field recordings in mouse brain slices (C57Bl/6, male and female). Immunohistochemistry for histamine-containing axons reveals striatal histaminergic innervation by the second postnatal week, and qRT-PCR shows transcripts for H1, H2, and H3 histamine receptors in striatum from the first postnatal week onwards, with pronounced developmental increases in H3 receptor expression. Whole-cell patch-clamp recordings of striatal spiny projection neurons and histamine superfusion demonstrates expression of functional histamine receptors from the first postnatal week onwards, with histamine having diverse effects on their electrical properties, including depolarization of the membrane potential while simultaneously decreasing action potential output. Striatal field recordings and electrical stimulation of corticostriatal afferents revealed that histamine, acting at H3 receptors, negatively modulates corticostriatal synaptic transmission from the first postnatal week onwards. Last, we investigated effects of histamine on longer-term changes at developing corticostriatal synapses and show that histamine facilitates NMDA receptor-dependent LTP via H3 receptors during the second postnatal week, but inhibits synaptic plasticity at later developmental stages. Together, these results show that histamine acutely modulates developing striatal neurons and synapses and controls longer-term changes in developing corticostriatal circuits, thus providing insight into the possible etiology underlying neurodevelopmental disorders resulting from histamine dysregulation.SIGNIFICANCE STATEMENT Monogenic causes of neurologic disorders, although rare, can provide opportunities to both study and understand the brain. For example, a nonsense mutation in the coding gene for the histamine-synthesizing enzyme has been associated with Tourette's syndrome and obsessive-compulsive disorder, and dysfunction of corticostriatal circuits. Nevertheless, the etiology of these neurodevelopmental disorders and histamine's role in the development of corticostriatal circuits have remained understudied. Here we show that histamine is an active neuromodulator during the earliest periods of postnatal life and acts at developing striatal neurons and synapses. Crucially, we show that histamine permits NMDA receptor-dependent corticostriatal synaptic plasticity during an early critical period of postnatal development, which suggests that genetic or environmental perturbations of histamine levels can impact striatal development.

Admixing MPTP-resistant and MPTP-vulnerable mice enhances striatal field potentials and calbindin-D28K expression to avert motor behaviour deficits

Asian-Indians are less vulnerable to Parkinson’s disease (PD) than the Caucasians. Their admixed populace has even lesser risk. Studying this phenomenon using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-susceptible C57BL/6J, MPTP-resistant CD-1 and their resistant crossbred mice revealed differences in the nigrostriatal cyto-molecular features. Here, we investigated the electrophysiological and behavioural correlates for differential MPTP-susceptibility and their outcome upon admixing. We recorded local field potentials (LFPs) from dorsal striatum and assessed motor co-ordination using rotarod and grip strength measures. Nigral calbindin-D28K expression, a regulator of striatal activity through nigrostriatal projections was evaluated using immunohistochemistry.The crossbreds had significantly higher baseline striatal LFPs. MPTP significantly increased the neuronal activity in delta (0.5–4 Hz) and low beta (12–16 Hz) ranges in C57BL/6J; significant increase across frequency bands till high beta (0.5–30 Hz) in CD-1, and caused no alterations in crossbreds. MPTP further depleted the already low nigral calbindin-D28K expression in C57BL/6J. While in crossbreds, it was further up-regulated. MPTP affected the rotarod and grip strength performance of the C57BL/6J, while the injected CD-1 and crossbreds performed well. The increased striatal β-oscillations are comparable to that in PD patients. Higher power in CD-1 may be compensatory in nature, which were also reported in pre-symptomatic monkeys. Concurrent up-regulation of nigral calbindin-D28K may assist maintenance of striatal activity by buffering calcium overload in nigra. Thus, preserved motor behaviour in PD reminiscent conditions in CD-1 and crossbreds complement compensated/unaffected striatal LFPs. Similar electrophysiological correlates and cytomorphological features are envisaged in human phenomenon of differential PD prevalence, which are modulated upon admixing.

Neuroprotective effects of adenosine deaminase in the striatum

Adenosine deaminase (ADA) is a ubiquitous enzyme that catabolizes adenosine and deoxyadenosine. During cerebral ischemia, extracellular adenosine levels increase acutely and adenosine deaminase catabolizes the increased levels of adenosine. Since adenosine is a known neuroprotective agent, adenosine deaminase was thought to have a negative effect during ischemia. In this study, however, we demonstrate that adenosine deaminase has substantial neuroprotective effects in the striatum, which is especially vulnerable during cerebral ischemia. We used temporary oxygen/glucose deprivation (OGD) to simulate ischemia in rat corticostriatal brain slices. We used field potentials as the primary measure of neuronal damage. For stable and efficient electrophysiological assessment, we used transgenic rats expressing channelrhodopsin-2, which depolarizes neurons in response to blue light. Time courses of electrically evoked striatal field potential (eFP) and optogenetically evoked striatal field potential (optFP) were recorded during and after oxygen/glucose deprivation. The levels of both eFP and optFP decreased after 10 min of oxygen/glucose deprivation. Bath-application of 10 µg/ml adenosine deaminase during oxygen/glucose deprivation significantly attenuated the oxygen/glucose deprivation-induced reduction in levels of eFP and optFP. The number of injured cells decreased significantly, and western blot analysis indicated a significant decrease of autophagic signaling in the adenosine deaminase-treated oxygen/glucose deprivation slices. These results indicate that adenosine deaminase has protective effects in the striatum.

Inhibition of presynaptic calcium transients in cortical inputs to the dorsolateral striatum by metabotropic GABA(B) and mGlu2/3 receptors.

Cortical inputs to the dorsolateral striatum (DLS) are dynamically regulated during skill learning and habit formation, and are dysregulated in disorders characterized by impaired action control. Therefore, a mechanistic investigation of the processes regulating corticostriatal transmission is key to understanding DLS-associated circuit function, behaviour and pathology. Presynaptic GABA(B) and group II metabotropic glutamate (mGlu2/3) receptors exert marked inhibitory control over corticostriatal glutamate release in the DLS, yet the signalling pathways through which they do so are unclear. We developed a novel approach using the genetically encoded calcium (Ca(2+) ) indicator GCaMP6 to assess presynaptic Ca(2+) in corticostriatal projections to the DLS. Using simultaneous photometric presynaptic Ca(2+) and striatal field potential recordings, we report that relative to P/Q-type Ca(2+) channels, N-type channels preferentially contributed to evoked presynaptic Ca(2+) influx in motor cortex projections to, and excitatory transmission in, the DLS. Activation of GABA(B) or mGlu2/3 receptors inhibited both evoked presynaptic Ca(2+) transients and striatal field potentials. mGlu2/3 receptor-mediated depression did not require functional N-type Ca(2+) channels, but was attenuated by blockade of P/Q-type channels. These findings reveal presynaptic mechanisms of inhibitory modulation of corticostriatal function that probably contribute to the selection and shaping of behavioural repertoires.

Interferon-β1a protects neurons against mitochondrial toxicity via modulation of STAT1 signaling: Electrophysiological evidence

Multiple sclerosis, one of the main causes of non-traumatic neurological disability in young adults, is an inflammatory and neurodegenerative disorder of the central nervous system. Although the pathogenesis of neuroaxonal damage occurring during the course of the disease is still largely unknown, there is accumulating evidence highlighting the potential role of mitochondria in multiple sclerosis-associated neuronal degeneration. The aim of the present study was to investigate, by utilizing electrophysiological techniques in brain striatal slices, the potential protective effects of interferon-β1a, one of the most widely used medication for multiple sclerosis, against acute neuronal dysfunction induced by mitochondrial toxins. Interferon-β1a was found to exert a dose-dependent protective effect against the progressive loss of striatal field potential amplitude induced by the mitochondrial complex I inhibitor rotenone. Interferon-β1a also reduced the generation of the rotenone-induced inward current in striatal spiny neurons. Conversely, interferon-β1a did not influence the electrophysiological effects of the mitochondrial complex II inhibitor 3-nitropropionic acid. The protective effect of interferon-β1a against mitochondrial complex I inhibition was found to be dependent on the activation of STAT1 signaling. Conversely, endogenous dopamine depletion and the modulation of the p38 MAPK and mTOR pathways did not influence the effects of interferon-β1a. During experimental autoimmune encephalomyelitis (EAE) striatal rotenone toxicity was enhanced but the protective effect of interferon-β1a was still evident.These results support future studies investigating the role played by specific intracellular signaling pathways in mediating the potential link among inflammation, mitochondrial impairment and neuroaxonal degeneration in multiple sclerosis.

Calbindin expression in developing striatum of zebra finches and its relation to the formation of area X

A sexually dimorphic network of brain regions controls learning and production of song in zebra finches. How this specialized song system evolved is unknown. To start addressing this question, we focused on developmental differences between the sexes, using the expression of the calcium-binding protein calbindin (CB) during embryonic to adult stages to map out the early development of Area X, a male-specific striatal structure. We related this pattern to the expression of three transcription factors, Pax6 and Islet1 to delineate the striatal radial domains, and Nkx2.1 as a marker for cells of pallidal origin. An incipient Area X-CB+ domain became discernable at embryonic day 13 in the Islet1-ventral striatal field. This region contained many Nkx2.1-expressing cells with a morphology characteristic of migrating cells. Eight days after hatching (PHD) CB staining clearly delineated Area X. Another CB+ structure formed around PHD5 at the subpallial/pallial boundary. We call it the CB+striatal capsule (CB-StC) and discuss its relation with the previously described striatal capsule in vertebrates. The CB cell population in both Area X and CB-StC, but not in the surrounding striatum, colocalized with the striatal medium spiny neurons (MSNs) marker, D1-receptor associated signaling protein dopamine-and-cAMP-regulated phosphoprotein of 32 kDa, DARPP32. In females, CB-positive cells were also present in the rostral striatum but did not coalesce into an Area X-like structure. We discuss possible reasons for CB expression in MSNs in songbirds and mammals, but not described in chicken striatum.

Origin and Properties of Striatal Local Field Potential Responses to Cortical Stimulation: Temporal Regulation by Fast Inhibitory Connections

Evoked striatal field potentials are seldom used to study corticostriatal communication in vivo because little is known about their origin and significance. Here we show that striatal field responses evoked by stimulating the prelimbic cortex in mice are reduced by more than 90% after infusing the AMPA receptor antagonist CNQX close to the recording electrode. Moreover, the amplitude of local field responses and dPSPs recorded in striatal medium spiny neurons increase in parallel with increasing stimulating current intensity. Finally, the evoked striatal fields show several of the basic known properties of corticostriatal transmission, including paired pulse facilitation and topographical organization. As a case study, we characterized the effect of local GABAA receptor blockade on striatal field and multiunitary action potential responses to prelimbic cortex stimulation. Striatal activity was recorded through a 24 channel silicon probe at about 600 µm from a microdialysis probe. Intrastriatal administration of the GABAA receptor antagonist bicuculline increased by 65±7% the duration of the evoked field responses. Moreover, the associated action potential responses were markedly enhanced during bicuculline infusion. Bicuculline enhancement took place at all the striatal sites that showed a response to cortical stimulation before drug infusion, but sites showing no field response before bicuculline remained unresponsive during GABAA receptor blockade. Thus, the data demonstrate that fast inhibitory connections exert a marked temporal regulation of input-output transformations within spatially delimited striatal networks responding to a cortical input. Overall, we propose that evoked striatal fields may be a useful tool to study corticostriatal synaptic connectivity in relation to behavior.

State-dependent plasticity of the corticostriatal pathway

Plasticity at corticostriatal synapses is thought to underlie both normal and aberrant forms of reinforcement-driven learning. Studies in brain slices have found bidirectional, spike-timing dependent plasticity in striatum; however it is not known whether similar rules govern corticostriatal plasticity in awake behaving animals. To assess whether behavioral state is a key regulator of plasticity in this pathway, we examined the effects of 5 Hz cortical stimulation trains on evoked striatal field potentials, in either anesthetized or awake, unrestrained rats. Consistent with prior studies we observed long-term potentiation in intact, barbiturate-anesthetized animals. However, when an identical stimulation pattern was applied to the same animals while awake, long-term depression was observed instead. Our results demonstrate that the rules governing corticostriatal plasticity depend critically on behavioral state, and suggest that the dynamic context of cortical-basal ganglia loops must be considered while investigating synaptic mechanisms underlying reinforcement learning and neurological disorders.

Induction of heat shock protein 70 reduces the alteration of striatal electrical activity caused by mitochondrial impairment

Since mild thermal stress seems to exert neuroprotection via induction of heat-shock protein 70 kDa (hsp70), we tested whether hsp70 would preserve striatal bioelectrical activity under conditions of mitochondrial impairment. Corticostriatal slices from rats that had undergone mild thermal stress were exposed to either rotenone or 3-nitropropionic acid (3-NP), that selectively inhibits mitochondrial complex I and complex II, respectively. Rotenone is utilized to obtain an experimental model of Parkinson's disease while 3-NP replicates Huntington's disease phenotype in experimental animals. The cerebral hsp70 increase did not alter field potential amplitude of the slices but partially protected them against rotenone-induced neurotoxicity. Similarly, induction of hsp70 had also a partial neuroprotective effect on the neurotoxicity caused by 3-NP on striatal field potential. Since rotenone and 3-NP treatments mimic the mitochondrial impairment and oxidative stress that contribute to development of Parkinson's disease and Huntington's disease, these data suggest that induction of hsp70 might represent a possible neuroprotective mechanism against the pathophysiological chain of events implicated in these neurodegenerative disorders.

Location and head direction representation in the dorsal striatum of rats

The activity of dorsal striatal location and head direction neurons were recorded as rats performed a hippocampal-dependent spatial working memory task. Relative to previous descriptions of hippocampal fields, striatal fields appeared more dependent on the visual environment in which the maze was performed. Striatal head direction correlates were also shown to be dependent upon the visual context in a lit environment: The directional preferences rotated with the rotation of distal visual cue, and maze or rat rotations had no effect. However, when animals performed the maze in darkness, idiothetic information gained greater control over head direction preferences: Passive movement of the rat in darkness (but not in light) disrupted directional firing. During both light and dark trials, the same head direction preferences were observed. A special contribution of the dorsal striatum to navigation may be to facilitate an animal’s ability to switch between navigational strategies, thereby maintaining behavioral constancy in changing environments.

Reelin mRNA expression during mouse brain development.

Using in situ hybridization, expression of the mRNA for reelin, the gene most probably responsible for the reeler trait, was studied during mouse brain development, from embryonic day 13 to maturity. The highest level of expression was found in Cajal-Retzius neurons, while a high signal was also seen in the olfactory bulb, the external granular layer of the cerebellum and, particularly at early developmental stages, in hypothalamic differentiation fields, tectum and spinal cord. A moderate to low level of expression was found in the septal area, striatal fields, habenular nuclei, some thalamic nuclei, particularly the lateral geniculate, the retina and some nuclei of the reticular formation in the central field of the medulla. Paradoxically, no reelin expression was detected in radial glial cells, the cortical plate, Purkinje cells, inferior olivary neurons and many other areas that are characteristically abnormal in reeler mutant mice. Together with other preliminary studies, the present observations suggest that the action of reelin is indirect, possibly mediated by the extracellular matrix. Most of the data can be explained by supposing that reelin is a cell-repulsive molecule which prevents migrating neurons from invading reelin-rich areas, and thus facilitates the deployment of radial glial cell processes and the formation of early architectonic patterns.

Evoked neuronal activity accompanied by transmitter release increases oxygen concentration in rat striatum in vivo but not in vitro.

Dopamine and oxygen (O2) were measured in the caudate nucleus of anesthetized rats and in striatal slices during electrical stimulation. Simultaneous electrochemical detection of dopamine and O2 was accomplished with fast-scan cyclic voltammetry at a Nafion-coated carbon-fiber microelectrode. Stimulation of the medial forebrain bundle resulted in synaptic overflow of dopamine in the caudate nucleus. At the same time, O2 concentration increased in the extracellular fluid with two separate phases. The amplitude of the initial increase directly correlated with the frequency of the stimulus, with the time of maximum concentration reproducible across a range of frequencies. The second increase occurred at later times with a more random amplitude and with a broad, variable shape. Agents which blocked vasodilation affected both phases: atropine attenuated the initial increase, while the second feature was nearly absent after theophylline. Yohimbine and alpha-methyl-p-tyrosine did not affect the O2 responses. Local electrical stimulation of the slice preparation also resulted in dopamine overflow, but a prolonged decrease in O2 concentration accompanied this event. Striatal field stimulation in vivo produced changes in O2 concentration dependent on the relative position of the stimulating and working electrodes, but none of the responses resembled that seen in the caudate slice. Thus, while measurements in brain slices show O2 consumption as a result of stimulated neuronal activity, an apparent elevation of local cerebral blood flow during and after stimulation dominate the in vivo response.

A simple ordering of neocortical areas established by the compartmental organization of their striatal projections.

The compartmental organization of corticostriatal projections from the fronto-orbito-insular cortex was studied in the cat. Cortical areas in this field were found to have a highly organized projection to the striatum, selectively innervating striosomes dorsally and predominantly avoiding them ventrally within their striatal fields of termination. These observations have two important implications for striatal processing. First, some cortical areas preferentially terminate in different compartments in different parts of the striatum. Therefore, the sources of input to striosomes and matrix are not categorical but switch according to the striatal region considered. Second, three properties of the bicompartmental termination pattern--one-dimensionality, common polarization, and multiple positions at which the pattern switched from "fills" to "avoids"--allowed us to order the corticostriatal projections with respect to one another. This ordering of the striatal projections of cortical areas implies an ordering of the cortical areas themselves, one that is independent of transcortical connections. For the corticostriatal projections described in this report, the ordering is [parietal, dorsomedial prefrontal, ventrolateral prefrontal, insular, rostral temporal] cortex. Our analysis suggests that a major function of striatal compartmentalization is to segregate and then bring together inputs from cortical areas at different positions in this ordering. The ordering may also serve as a simple format for specifying corticostriatal connections in development.

Interruption of projections from the medial geniculate body to an archi-neostriatal field disrupts the classical conditioning of emotional responses to acoustic stimuli

We have previously found that the coupling of changes in autonomie activity and emotional behavior to acoustic stimuli through classical fear conditioning survives bilateral ablation of auditory cortex but is disrupted by bilateral lesions of the medial geniculate nucleus or inferior colliculus in rats. Auditory fear conditioning thus appears to be mediated by the relay of acoustic input from the medial geniculate nucleus to subcortical rather than cortical targets. Since the medial geniculate nucleus projects, in addition to auditory cortex, to a striatal field, involving portions of the posterior neostriatum and underlying archistriatum (amygdala), we have sought to determine whether interruption of connections linking the medial geniculate nucleus to this subcortical field also disrupts conditioning. The conditioned emotional response model studied included the measurement of increases in mean arterial pressure and heart rate and the suppression of exploratory activity and drinking by the acoustic conditioned stimulus following delayed classical conditioning, where the footshock unconditioned stimulus appeared at the end of the conditioned stimulus. The peak increase in arterial pressure and the duration of activity and drinking suppression were greater in unoperated animals subjected to delayed conditioning than in pseudoconditioned controls, where the footshock was randomly rather than systematically related to the acoustic stimulus. Increases in heart rate, however, did not differ in conditioned and pseudoconditioned groups. While the arterial pressure and behavioral responses therefore reflect associative conditioning, the heart rate response does not. Rats were prepared with bilateral lesions of the medial geniculate nucleus, bilateral lesions of the striatal field or asymmetrical unilateral lesions destroying the medial geniculate nucleus on one side and the striatal field on the contralateral side. The latter preparation leaves one medial geniculate nucleus and one striatal field intact but disconnected and thus produces a selective auditory deafferentation of the intact striatal field. Control groups included animals with unilateral lesion of the medial geniculate nucleus, with unilateral lesion of the medial geniculate nucleus combined with lesion of the ipsilateral striatal field, unilateral lesion of the medial geniculate combined with lesion of the contralateral anterior neostriatum (a striatal area outside of the medial geniculate nucleus projection field), and the unilateral lesion of the medial geniculate nucleus combined with lesion of the contralateral ventromedial hypothalamus or subparafascicular thalamus (regions which receive projections from areas adjacent to the medial geniculate nucleus, but not from the medial geniculate nucleus itself). Bilateral lesions of the medial geniculate nucleus and bilateral lesions of the striatal field both drastically reduced the magnitude of the learned changes in arterial pressure and the duration of activity and drink suppression elicited by the conditioned stimulus. However, the nonassociative heart rate increase persisted. Asymmetric lesions involving one medial geniculate nucleus and the contralateral striatal field also disrupted the arterial pressure and behavioral, but not the heart rate, response. Lesions involving one medial geniculate nucleus and the ipsilateral striatal field did not disrupt any of the responses, nor did combined lesions involving one medial geniculate nucleus and the contralateral anterior neostriatum, ventromedial hypothalamus, or subparafascicular thalamus. Thus, bilateral destruction of either the medial geniculate nucleus or the striatal field or interruption of projections linking the medial geniculate nucleus to the striatal field disrupts associative changes in autonomie activity and behavior elicited by an acoustic conditioned stimulus. We conclude that auditory fear conditioning is mediated by efferent connections linking the medial geniculate nucleus to a striatal field, a subcortical projection field involving the posterior caudate-putamen (neostriatum) and/or amygdala (archistriatum). These connections are necessary for the establishment of associatively conditioned autonomie and somatomotor responses to an acoustic stimulus but do not appear to mediate nonassociative (pseudoconditioned) responses elicited by the same stimulus.