Key points
Neural synchrony between the subthalamic nucleus (STN) and cortex is critical for proper information processing in basal ganglia circuits.
Using in vivo extracellular recordings in ...urethane‐anaesthetized mice, we demonstrate that single units and local field potentials from the STN exhibit oscillatory entrainment to low‐frequency (0.5–4 Hz) rhythms when the cortex is in a synchronized state.
Here we report novel findings in the R6/2 transgenic mouse model of Huntington's disease (HD) by demonstrating that STN activity is reduced and less phase‐locked to cortical low‐frequency oscillations.
The spectral power of low‐frequency oscillations in ECoG recordings of R6/2 mice is diminished while the spectral power of higher frequencies is augmented and such altered cortical patterning could lead to decreased synchrony in corticosubthalamic circuits.
Our data establish that cortical entrainment of STN neural activity is disrupted in R6/2 mice and may be one of the mechanisms contributing to disordered motor control in HD.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder in which impairments in the processing of information between the cortex and basal ganglia are fundamental to the onset and progression of the HD phenotype. The corticosubthalamic hyperdirect pathway plays a pivotal role in motor selection and blockade of neuronal activity in the subthalamic nucleus (STN) results in a hyperkinetic movement syndrome, similar to the HD phenotype. The aim of the present study was to examine the relationship between neuronal activity in the STN and cortex in an animal model of HD. We performed in vivo extracellular recordings in the STN to measure single‐unit activity and local field potentials in the R6/2 transgenic mouse model of HD. These recordings were obtained during epochs of simultaneously acquired electrocorticogram (ECoG) in discrete brain states representative of global cortical network synchronization or desynchronization. Cortically patterned STN neuronal activity was less phase‐locked in R6/2 mice, which is likely to result in less efficient coding of cortical inputs by the basal ganglia. In R6/2 mice, the power of the ECoG in lower frequencies (0.5–4 Hz) was diminished while the power expressed in higher frequencies (13–100 Hz) was increased. In addition, the spontaneous activity of STN neurons in R6/2 mice was reduced and neurons exhibited a more irregular firing pattern. Glutamatergic STN neurons provide the major excitatory drive to the output nuclei of the basal ganglia and altered discharge patterns could lead to aberrant basal ganglia output and disordered motor control in HD.
Abstract Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that results in motor, cognitive and psychiatric abnormalities. Dysfunction in neuronal processing between the ...cortex and the basal ganglia is fundamental to the onset and progression of the HD phenotype. The corticosubthalamic hyperdirect pathway plays a crucial role in motor selection and blockade of neuronal activity in the subthalamic nucleus (STN) results in hyperkinetic movement abnormalities, similar to the motor symptoms associated with HD. The aim of the present study was to examine whether changes in the fidelity of information transmission between the cortex and the STN emerge as a function of phenotypic severity in the YAC128 mouse model of HD. We obtained in vivo extracellular recordings in the STN and concomitant electrocorticogram (ECoG) recordings during discrete brain states that reflected global cortical network synchronization or desynchronization. At early ages in YAC128 mice, both the cortex and the STN exhibited patterns of hyperexcitability. As symptom severity progressed, cortical entrainment of STN activity was disrupted and there was an increase in the proportion of non-oscillating, tonically firing STN neurons that were less phase-locked to cortical activity. Concomitant to the dissipation of STN entrainment, there was a reduction in the evoked response of STN neurons to focal cortical stimulation. The spontaneous discharge of STN neurons in YAC128 mice also decreased with age and symptom severity. These results indicate dysfunction in the flow of information within the corticosubthalamic circuit and demonstrate progressive age-related disconnection of the hyperdirect pathway in a transgenic mouse model of HD.
Basal ganglia macrocircuits Tepper, J M; Abercrombie, E D; Bolam, J P
Progress in brain research,
2007, Letnik:
160
Journal Article
Recenzirano
This is the introductory chapter to an edited volume comprising 18 chapters written by 38 specially selected authors covering the anatomy, physiology, biochemistry/pharmacology and behavioral aspects ...of GABA in the basal ganglia. In this chapter the various nuclei of the basal ganglia are defined and their cellular structure, connections and function reviewed in brief in order to provide an orientation for the subsequent 17 chapters.
Huntington's disease (HD) is characterized by numerous alterations within the corticostriatal circuitry. The striatum is innervated by a dense array of dopaminergic (DA) terminals and these DA ...synapses are critical to the proper execution of motor functions. As motor disturbances are prevalent in HD we examined DA neurotransmission in the striatum in transgenic (tg) murine models of HD. We used in vivo microdialysis to compare extracellular concentrations of striatal DA in both a fragment (R6/2) model, which displays a rapid and severe phenotype, and a full-length (YAC128) model that expresses a more progressive phenotype. Extracellular striatal DA concentrations were significantly reduced in R6/2 mice and decreased concomitantly with age-dependent increasing motor impairments on the rotarod task (7, 9, and 11 weeks). In a sample of 11-week-old R6/2 mice, we also measured tissue concentrations of striatal DA and found that total levels of DA were significantly depleted. However, the loss of total DA content (<50%) was insufficient to account for the full extent of DA depletion in the extracellular fluid (ECF; ∼75%). We also observed a significant reduction in extracellular DA concentrations in the striatum of 7-month-old YAC128 mice. In a separate set of experiments, we applied d-amphetamine (AMPH; 10 μm) locally into the striatum to stimulate the release of intracellular DA into the ECF. The AMPH-induced increase in extracellular DA levels was significantly blunted in 9-week-old R6/2 mice. There also was a decrease in AMPH-stimulated DA efflux in 7-month-old YAC128 mice in comparison to WT controls, although the effect was milder. In the same cohort of 7-month-old YAC128 mice we observed a significant reduction in the total locomotor activity in response to systemic AMPH (2 mg/kg). Our data demonstrate that extracellular DA release is attenuated in both a fragment and full-length tg mouse model of HD and support the concept of DA involvement in aspects of the syndrome.
Nuclei within the basal ganglia—such as the globus pallidus external segment, subthalamic nucleus, and substantia nigra pars reticulata—have been shown to exhibit synchronous bursting activity ...entrained to excessive cortical beta oscillations following dopamine depletion. Zolpidem binds to GABAA receptors with selectivity for those expressing the α1 subunit, potentiating inhibitory postsynaptic currents and increasing the time decay of channel opening. Interestingly, zolpidem‐sensitive nuclei within the basal ganglia circuitry are also those that have been shown to exhibit hyperexcitation in a dopamine‐depleted state. We hypothesized that a drug with selectivity for these nuclei may improve motor impairments associated with Parkinson's disease. In order to determine the threshold dose at which zolpidem might encumber motor behavior, a dose‐response experiment was performed in intact rats using rotarod. Next, we tested whether subthreshold doses (0.1, 0.25, 0.5 mg/kg; i.p.) of zolpidem improved volitional motor behavior/coordination using the rotarod balance beam and cylinder/paw preference tests in unilaterally 6‐hydroxydopamine‐lesioned rats. It was found that 0.1 mg/kg zolpidem significantly improved rotarod performance and significantly reduced forelimb use asymmetry compared to undrugged post‐lesion conditions. Here, we present the first translational evidence for a role of zolpidem‐sensitive GABAA receptors in the treatment of PD motor symptoms. Our data show that zolpidem improves both motor coordination and volitional forelimb use in the unilateral 6‐hydroxydopamine lesion model of PD, and thus suggest that zolpidem‐sensitive GABAA receptors may represent a novel therapeutic target for the treatment of motor symptoms of Parkinson's disease.
Extrastriatal basal ganglia nuclei have been shown to exhibit synchronous bursting activity entrained to cortical beta oscillations following dopamine depletion. The expression of zolpidem‐sensitive GABAA receptors appears to overlap with this pathophysiology. This study represents the first translational evidence that GABAA receptors expressing the α1 subunit may represent a novel therapeutic target in the treatment of motor symptoms of Parkinson's disease.
Striatal cholinergic interneurons play a pivotal role in the integrative sensorimotor functions of the basal ganglia. The major excitatory input to these interneurons arises from glutamatergic ...neurons of the parafascicular nucleus of the thalamus (Pf). Thalamic regulation of cholinergic interneurons, however, may also include an indirect inhibitory component mediated by the axon collaterals of GABAergic medium spiny neurons that are also innervated by Pf. The present study examined thalamic regulation of striatal cholinergic interneurons by employing dual probe
in vivo microdialysis in freely moving animals to determine the effect of pharmacological manipulation of Pf on acetylcholine (ACh) efflux in intact and dopamine-lesioned striata.
In intact animals, reverse dialysis application of the GABA
A antagonist bicuculline (50 μM) into Pf, likely disinhibiting Pf neurons, significantly decreased striatal ACh efflux. When striatal GABA
A receptors were blocked by simultaneous reverse dialysis application of bicuculline (10 μM), however, the same manipulation significantly increased ACh efflux. Qualitatively similar results were obtained in experiments employing a higher concentration of bicuculline (200 μM). Application of the GABA agonist muscimol (500 μM) into Pf, likely inhibiting Pf neurons, decreased ACh efflux only when the experiment was conducted under blockade of striatal GABA
A receptors. These data are consistent with the existence of an indirect, inhibitory, GABA
A receptor-mediated component of ACh regulation that is most clearly manifested when Pf is disinhibited and with the existence of a direct excitatory component of ACh regulation, evident when Pf is inhibited. Manipulation of Pf using very high concentrations of drug (500 μM bicuculline, 2 mM muscimol), however, yielded data consistent only with direct excitatory thalamic regulation.
In contrast to results obtained in intact animals, in animals with prior (3 weeks) unilateral lesion of the dopaminergic nigrostriatal pathway, bicuculline application (50 μM) in Pf significantly increased striatal ACh efflux, irrespective of simultaneous blockade of striatal GABA
A receptors. The results of experiments in which muscimol (500 μM) was applied in Pf were similar to those obtained in intact animals, however. Baseline ACh efflux was not significantly elevated in dopamine-lesioned animals.
These results indicate a qualitative alteration in the effectiveness of an inhibitory component of the thalamic regulation of ACh efflux in the dopamine depleted striatum, evident during increased thalamostriatal input. Such altered regulation of striatal ACh output is likely to have profound consequences for integrative function in the parkinsonian basal ganglia.
The relationship between discharge rates of locus coeruleus noradrenergic neurons and rates of norepinephrine release was examined in the anesthetized rat. Neuronal discharge rates of locus coeruleus ...neurons were altered and quantified using a combined recording-infusion probe. Peri-locus coeruleus infusions of either the cholinergic agonist, bethanechol, or the α
2-agonist, clonidine, were used to enhance or suppress neuronal discharge activity, respectively. Alterations in concentrations of extracellular norepinephrine within the prefrontal cortex were determined using
in vivo microdialysis and high-pressure liquid chromatography with electrochemical detection. A linear relationship between locus coeruleus activity and norepinephrine dialysate concentration was observed between complete suppression of locus coeruleus discharge activity and approximately 300–400% of basal discharge levels (1.58±0.29
Hz). Above these levels, increases in locus coeruleus discharge rates were not accompanied by similar increases in dialysate norepinephrine concentrations. In general, neither activation nor suppression of locus coeruleus neuronal discharge rates appeared to alter the relationship between discharge activity and norepinephrine efflux during subsequent epochs. The one exception to this was observed during recovery from relatively high-magnitude locus coeruleus activation. In two out of three cases in which locus coeruleus discharge rates were increased greater than 450%, a recovery of norepinephrine concentrations to basal levels occurred more quickly than the recovery of locus coeruleus neuronal discharge rates to basal levels.
Although limited, these latter observations suggest that dysregulation of norepinephrine release may occur following sustained activation of locus coeruleus at the highest rates examined, which may mimic those associated with intense arousal or stress.
We have examined the effects of diazepam on the stress-induced increase in extracellular dopamine and norepinephrine in the medial prefrontal cortex using in vivo microdialysis. In naive rats, acute ...tail pressure (30 min) elicited an increase in the concentrations of dopamine and norepinephrine in extracellular fluid of medial prefrontal cortex (+54 and +50%, respectively). Diazepam (2.5 mg/kg, i.p.) decreased the basal concentration of extracellular dopamine and norepinephrine. Diazepam also attenuated the stress-evoked increase in the absolute concentrations of extracellular dopamine (+17%), but did not alter the stress-induced increase in norepinephrine (+41%). However, when the drug-induced decrease in basal dopamine and norepinephrine concentration was taken into account, the stress-induced net increase in dopamine above the new baseline was equivalent to that obtained in vehicle pretreated rats, whereas the net increase in norepinephrine was almost twice that obtained in control subjects. In rats previously exposed to chronic cold (three to four weeks at 5 degrees C), tail pressure again produced an increase in the concentrations of dopamine and norepinephrine in the medial prefrontal cortex (+42% and +92%, respectively). However, in these chronically stressed rats, diazepam no longer decreased basal dopamine or norepinephrine in extracellular fluid, nor did it affect the stress-induced increase in the concentrations of these catecholamines. These data indicate that diazepam has complex effects on the extracellular concentrations of dopamine and norepinephrine which vary depending upon whether the rat is undisturbed or stressed during the period of drug exposure as well as the rat's prior history of exposure to stress. Moreover, these data raise questions regarding the role of catecholamines in the mechanism by which diazepam exerts its anxiolytic properties.
The differential behavioral and neurochemical effects of exogenous L-DOPA in animals with intact versus dopamine (DA)-denervated striata raise questions regarding the role of DA terminals in the ...regulation of dopaminergic neurotransmission after administration of exogenous L-DOPA. In vivo microdialysis was used to monitor the effect of exogenous L-DOPA on extracellular DA in intact and DA-denervated striata of awake rats. In intact striatum, a small increase in extracellular DA was observed after administration of L-DOPA (50 mg/kg i.p.) but in DA-denervated striatum a much larger increase in extracellular DA was elicited. Additional experiments assessed the role of high-affinity DA uptake and impulse-dependent neurotransmitter release in the effect of exogenous L-DOPA on extracellular DA in striatum. Pretreatment with GBR-12909 (20 mg/kg i.p.), a selective DA uptake inhibitor, enhanced the ability of L-DOPA to increase extracellular DA in intact striatum. However, in DA-denervated striatum, inhibition of DA uptake did not alter the extracellular DA response to L-DOPA. Impulse-dependent neurotransmitter release was blocked by the infusion of tetrodotoxin (TTX; 1 microM), an inhibitor of fast sodium channels, through the dialysis probe. Application of TTX significantly attenuated the L-DOPA-induced increase in extracellular DA observed in striatum of intact rats pretreated with GBR-12909. In a similar manner, TTX infusion significantly attenuated the increase in extracellular DA typically observed in striatum of 6-OHDA-lesioned rats after the administration of L-DOPA. The present results indicate that DA terminals, via high-affinity uptake, play a crucial role in the clearance of extracellular DA formed from exogenous L-DOPA in intact striatum. This regulatory mechanism is absent in the DA-denervated striatum. In addition, this study has shown that DA synthesized from exogenous L-DOPA primarily is released by an impulse-dependent mechanism in both intact and DA-denervated striatum. The latter result suggests an important role for a nondopaminergic neuronal element in striatum that serves as the primary source of extracellular DA formed from exogenous L-DOPA.
Identifying the driving forces behind oceanic pelagic shark movements is key to a better understanding of their life history. Some oceanic pelagic shark species have been shown to aggregate in ...specific regions to mate and/or exploit abundant food resources. The oceanic whitetip shark Carcharhinus longimanus, a subtropical, ectothermic, oceanic pelagic shark that has experienced severe population declines, aggregates seasonally around Cat Island (CI) in The Bahamas. Large pelagic teleosts (e.g. billfish, tunas, and dolphinfish) are abundant in this region and oceanic whitetips are anecdotally reported to feed heavily on recreationally caught teleosts. However, it was unknown whether feeding habits at CI substantially differ from longer-term feeding habits. We used tag-recapture to assess site-fidelity of adult oceanic whitetips to CI and stable isotope analysis (SIA) of 2 different tissues (blood plasma and white muscle) to compare short- and long-term feeding patterns. The relatively high recapture rate (20.3%) confirmed that individual whitetips exhibit site-fidelity to CI. The aggregation consisted of adult individuals; females were more common, more than half were gravid, and no physical or behavioral evidence of mating or parturition was observed at CI. SIA-based Bayesian mixing model estimates of short-term (near CI) diets showed more large pelagic teleosts (72%) than in long-term diets (47%), showing a spatiotemporal difference in oceanic whitetip feeding habits. This suggests that availability of large teleost prey is a possible mechanism underpinning site-fidelity and aggregation of whitetips at CI. These results provide insight into the function of one of the last known aggregations of this once-abundant top predator.
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