A single dose of escitalopram blunts the neural response in the thalamus and caudate during monetary loss.

Background: Selective serotonin reuptake inhibitors (SSRIs) show acute effects on the neural processes associated with negative affective bias in healthy people and people with depression. However, whether and how SSRIs also affect reward and punishment processing on a similarly rapid time scale remains unclear. Methods: We investigated the effects of an acute and clinically relevant dose (20 mg) of the SSRI escitalopram on brain response during reward and punishment processing in 19 healthy participants. In a doubleblind, placebo-controlled study using functional MRI, participants performed a well-established monetary reward task at 3 time points: at baseline; after receiving placebo or escitalopram; and after receiving placebo or escitalopram following an 8-week washout period. Results: Acute escitalopram administration reduced blood-oxygen-level-dependent (BOLD) response during punishment feedback in the right thalamus (family-wise error corrected [FWE] p = 0.013 at peak level) and the right caudate head (pFWE = 0.011 at peak level) compared to placebo. We did not detect any significant BOLD changes during reward feedback. Limitations: We included only healthy participants, so interpretation of findings are limited to the healthy human brain and require future testing in patient populations. The paradigm we used was based on monetary stimuli, and results may not be generalizable to other forms of reward. Conclusion: Our findings extend theories of rapid SSRI action on the neural processing of rewarding and aversive stimuli and suggest a specific and acute effect of escitalopram in the punishment neurocircuitry.

Propofol rather than Isoflurane Accelerates the Interstitial Fluid Drainage in the Deep Rat Brain.

Objective: Different anesthetics have distinct effects on the interstitial fluid (ISF) drainage in the extracellular space (ECS) of the superficial rat brain, while their effects on ISF drainage in the ECS of the deep rat brain still remain unknown. Herein, we attempt to investigate and compare the effects of propofol and isoflurane on ECS structure and ISF drainage in the caudate-putamen (CPu) and thalamus (Tha) of the deep rat brain. Methods: Adult Sprague-Dawley rats were anesthetized with propofol or isoflurane, respectively. Twenty-four anesthetized rats were randomly divided into the propofol-CPu, isoflurane-CPu, propofol-Tha, and isoflurane-Tha groups. Tracer-based magnetic resonance imaging (MRI) and fluorescent-labeled tracer assay were utilized to quantify ISF drainage in the deep brain. Results: The half-life of ISF in the propofol-CPu and propofol-Tha groups was shorter than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. The ECS volume fraction in the propofol-CPu and propofol-Tha groups was much higher than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. However, the ECS tortuosity in the propofol-CPu and propofol-Tha groups was much smaller than that in isoflurane-CPu and isoflurane-Tha groups, respectively. Conclusions: Our results demonstrate that propofol rather than isoflurane accelerates the ISF drainage in the deep rat brain, which provides novel insights into the selective control of ISF drainage and guides selection of anesthetic agents in different clinical settings, and unravels the mechanism of how general anesthetics function.

Frontal eye field and caudate neurons make different contributions to reward-biased perceptual decisions.

Many decisions require trade-offs between sensory evidence and internal preferences. Potential neural substrates include the frontal eye field (FEF) and caudate nucleus, but their distinct roles are not understood. Previously we showed that monkeys' decisions on a direction-discrimination task with asymmetric rewards reflected a biased accumulate-to-bound decision process (Fan et al., 2018) that was affected by caudate microstimulation (Doi et al., 2020). Here we compared single-neuron activity in FEF and caudate to each other and to accumulate-to-bound model predictions derived from behavior. Task-dependent neural modulations were similar in both regions. However, choice-selective neurons in FEF, but not caudate, encoded behaviorally derived biases in the accumulation process. Baseline activity in both regions was sensitive to reward context, but this sensitivity was not reliably associated with behavioral biases. These results imply distinct contributions of FEF and caudate neurons to reward-biased decision-making and put experimental constraints on the neural implementation of accumulation-to-bound-like computations.

Reduced density of oligodendrocytes and oligodendrocyte clusters in the caudate nucleus in major psychiatric illnesses.

Functional dysconnectivity in schizophrenia and affective disorders may be associated with myelin and oligodendrocyte abnormalities. Altered network integration involving the caudate nucleus (CN) and metabolic abnormalities in fronto-striatal-thalamic white matter tracts have been reported in schizophrenia and impaired patterns of cortico-caudate functional connectivity have been found in both bipolar disorder (BPD) and schizophrenia compared to healthy controls. Postmortem studies have found ultrastructural dystrophy and degeneration of oligodendrocytes and dysmyelination in the CN in schizophrenia and BPD. We aimed to test the hypothesis that oligodendrocyte density may be reduced in the CN in major psychiatric disorders and may thereby form the cellular basis for the functional dysconnectivity observed in these disorders. Optical disector was used to estimate the numerical density (Nv) of oligodendrocytes and oligodendrocyte clusters (OLC) in the CN of cases with schizophrenia, BPD and major depressive disorder (MDD) and in normal controls (15 cases per group). A significant reduction in the Nv of oligodendrocytes was found in schizophrenia and BPD as compared to the control group (p < 0.05), and the Nv of OLC was significantly lowered in schizophrenia and BPD compared to controls (p < 0.05). There were no significant differences between MDD and control groups. The Nv of OLC was significantly decreased in the left hemisphere in schizophrenia as compared to the left hemisphere of the control group (-52%, p < 0.01). The data indicates that a decreased density of oligodendrocytes and OLC could contribute to the altered functional connectivity of the CN in subjects with severe mental illnesses.

Long-Term Fine Motor Capability on the Staircase Test Correlates with the Absolute Number, but Not the Density, of DARPP-Positive Neurons in the Caudate-Putamen.

Measurement of long-term functional and anatomical outcomes in the same animal is considered a powerful strategy for correlating structure with function. In a neonatal animal model of hypoxic-ischemic brain injury that is relevant to cerebral palsy, long-term functional deficits on the staircase test and long-term anatomical deficits in the absolute number of medium-spiny projection neurons in the caudate-putamen were reported in different animals due to logistical constraints. Here, we investigated if these functional and anatomical measures were correlated when measured in the same animals. The medium-spiny projection neurons were investigated because (1) they comprise the vast majority (>97%) of all neurons in the caudate-putamen and (2) motor deficits observed during staircase testing are likely to involve these striatal medium-spiny projection neurons through their connections. We found that long-term skilled forepaw capability on the staircase test was correlated with the absolute number of DARPP-32-positive medium-spiny projection neurons in the caudate-putamen. Specifically, deficits in skilled forepaw ability for the number of sugar pellets eaten and retrieved, and for the maximum staircase level reached, were significantly correlated with a lower absolute neuronal number. We also found that skilled forepaw ability on the staircase test was not correlated with the neuronal density (i.e., number per unit volume) of DARPP-32-positive medium-spiny projection neurons. Since neuronal density is an indirect measure of neuronal survival that is used in the literature, and absolute neuronal number is a direct measure, the results also highlight the scientific value of measuring absolute neuronal number. Anat Rec, 302:2040-2048, 2019. © 2019 American Association for Anatomy.

Mapping projections of molecularly defined dopamine neuron subtypes using intersectional genetic approaches.

Midbrain dopamine (DA) neurons have diverse functions that can in part be explained by their heterogeneity. Although molecularly distinct subtypes of DA neurons have been identified by single-cell gene expression profiling, fundamental features such as their projection patterns have not been elucidated. Progress in this regard has been hindered by the lack of genetic tools for studying DA neuron subtypes. Here we develop intersectional genetic labeling strategies, based on combinatorial gene expression, to map the projections of molecularly defined DA neuron subtypes. We reveal distinct genetically defined dopaminergic pathways arising from the substantia nigra pars compacta and from the ventral tegmental area that innervate specific regions of the caudate putamen, nucleus accumbens and amygdala. Together, the genetic toolbox and DA neuron subtype projections presented here constitute a resource that will accelerate the investigation of this clinically significant neurotransmitter system.

Different contributions of preparatory activity in the basal ganglia and cerebellum for self-timing.

The ability to flexibly adjust movement timing is important for everyday life. Although the basal ganglia and cerebellum have been implicated in monitoring of supra- and sub-second intervals, respectively, the underlying neuronal mechanism remains unclear. Here, we show that in monkeys trained to generate a self-initiated saccade at instructed timing following a visual cue, neurons in the caudate nucleus kept track of passage of time throughout the delay period, while those in the cerebellar dentate nucleus were recruited only during the last part of the delay period. Conversely, neuronal correlates of trial-by-trial variation of self-timing emerged earlier in the cerebellum than the striatum. Local inactivation of respective recording sites confirmed the difference in their relative contributions to supra- and sub-second intervals. These results suggest that the basal ganglia may measure elapsed time relative to the intended interval, while the cerebellum might be responsible for the fine adjustment of self-timing.

A common neural code for social and monetary rewards in the human striatum.

Although managing social information and decision making on the basis of reward is critical for survival, it remains uncertain whether differing reward type is processed in a uniform manner. Previously, we demonstrated that monetary reward and the social reward of good reputation activated the same striatal regions including the caudate nucleus and putamen. However, it remains unclear whether overlapping activations reflect activities of identical neuronal populations or two overlapping but functionally independent neuronal populations. Here, we re-analyzed the original data and addressed this question using multivariate-pattern-analysis and found evidence that in the left caudate nucleus and bilateral nucleus accumbens, social vs monetary reward were represented similarly. The findings suggest that social and monetary rewards are processed by the same population of neurons within these regions of the striatum. Additional findings demonstrated similar neural patterns when participants experience high social reward compared to viewing others receiving low social reward (potentially inducing schadenfreude). This is possibly an early indication that the same population of neurons may be responsible for processing two different types of social reward (good reputation and schadenfreude). These findings provide a supplementary perspective to previous research, helping to further elucidate the mechanisms behind social vs non-social reward processing.

Convergence of prefrontal and parietal anatomical projections in a connectional hub in the striatum.

Visual attentional bias forms for rewarding and punishing stimuli in the environment. While this attentional bias is adaptive in healthy situations, it is maladaptive in disorders such as drug addiction or PTSD. In both these disorders, the ability to exert control over this attentional bias is associated with drug abstinence rates or reduced PTSD symptoms, indicating the interaction of visual attention, cognitive control, and stimulus association. The inferior parietal lobule (IPL) is central to attention, while the prefrontal cortex (PFC) is critical for reward, cognitive control, and attention. Importantly, regions of the IPL and PFC commonly project to the rostral dorsal caudate (rdCaud) of the striatum. We propose an anatomical network architecture in which IPL projections converge with PFC projections in a connectional hub in the rdCaud, providing an anatomical substrate for the interaction of these projections and their competitive influence on striatal processing. To investigate this, we mapped the dense projections from the caudal IPL and prefrontal (dlPFC, vlPFC, OFC, dACC, and dmPFC) regions that project to the medial rdCaud with anatomical tract-tracing tracer injections in monkeys. These inputs converge in a precise site in the medial rdCaud, rostral to the anterior commissure. Small retrograde tracer injections confirmed these inputs to the medial rdCaud and showed that a proximal ventral striatal location has a very different pattern of cortical inputs. We next used human resting-state functional connectivity MRI (fcMRI) to examine whether a striatal hub exists in the human medial rdCaud. Seed regions in the human medial rdCaud revealed cortical correlation maps similar to the monkey retrograde injection results. A subsequent analysis of these correlated cortical regions showed that their peak correlation within the striatum is in the medial rdCaud, indicating that this is a connectional hub. In contrast, this peak striatal correlation was not found in the ventral striatal location, suggesting that this site is not a connectional hub of cortical regions. Taken together, this work uses the precision of monkey anatomy to identify a connectional hub of IPL and PFC projections in the medial rdCaud. It also translates this anatomical precision to humans, demonstrating that, guided by anatomy, connectional hubs can be identified in humans with fcMRI. These connectional hubs provide more specific treatment targets for drug addiction, PTSD, and other neurological and psychiatric disorders involving the striatum.

Endocannabinoid 2-Arachidonoylglycerol Suppresses LPS-Induced Inhibition of A-Type Potassium Channel Currents in Caudate Nucleus Neurons Through CB1 Receptor.

Inflammation plays a pivotal role in the pathogenesis of many diseases in the central nervous system. Caudate nucleus (CN), the largest nucleus in the brain, is also implicated in many neurological disorders. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid, has been shown to exhibit neuroprotective effects through its anti-inflammatory action from some proinflammatory stimuli. However, the neuroprotective mechanism of 2-AG is complex and has not been fully understood. A-type K(+) channels critically regulate neuronal excitability and have been demonstrated to be associated with some nervous system diseases. The aim of this study was to explore whether A-type K(+) channels were involved in neurotoxicity of lipopolysaccharides (LPS) and the neuroprotective mechanism of 2-AG in CN neurons. Whole cell patch clamp recording was used to investigate the influence of LPS on the function of A-type K(+) channels and its modulation by 2-AG in primary cultured rat CN neurons. Our findings showed that in cultured CN neurons, LPS significantly decreased the A-type potassium currents (I A) in a voltage-insensitive way. The further data demonstrated that an elevation of 2-AG levels by directly applying exogenous 2-AG or inhibiting monoacylglycerol lipase (MAGL) to prevent 2-AG hydrolysis was capable of suppressing the LPS-induced inhibition of IA and the action of 2-AG is mediated through CB1 receptor-dependant way. The study provides a better understanding of inflammation-related neurological disorders and suggests the therapeutic potential for 2-AG for the treatment of these diseases.

Activity of Caudate Nucleus Neurons in a Visual Fixation Paradigm in Behaving Cats.

Beside its motor functions, the caudate nucleus (CN), the main input structure of the basal ganglia, is also sensitive to various sensory modalities. The goal of the present study was to investigate the effects of visual stimulation on the CN by using a behaving, head-restrained, eye movement-controlled feline model developed recently for this purpose. Extracellular multielectrode recordings were made from the CN of two cats in a visual fixation paradigm applying static and dynamic stimuli. The recorded neurons were classified in three groups according to their electrophysiological properties: phasically active (PAN), tonically active (TAN) and high-firing (HFN) neurons. The response characteristics were investigated according to this classification. The PAN and TAN neurons were sensitive primarily to static stimuli, while the HFN neurons responded primarily to changes in the visual environment i.e. to optic flow and the offset of the stimuli. The HFNs were the most sensitive to visual stimulation; their responses were stronger than those of the PANs and TANs. The majority of the recorded units were insensitive to the direction of the optic flow, regardless of group, but a small number of direction-sensitive neurons were also found. Our results demonstrate that both the static and the dynamic components of the visual information are represented in the CN. Furthermore, these results provide the first piece of evidence on optic flow processing in the CN, which, in more general terms, indicates the possible role of this structure in dynamic visual information processing.

Ovarian steroids alter dopamine receptor populations in the medial preoptic area of female rats: implications for sexual motivation, desire, and behaviour.

Dopamine (DA) transmission in the medial preoptic area (mPOA) plays a critical role in the control of appetitive sexual behaviour in the female rat. We have shown previously that a DA D1 receptor (D1R)-mediated excitatory state appears to occur in females primed with estradiol benzoate (EB) and progesterone (P), whereas a DA D2 receptor (D2R)-mediated inhibitory state appears to occur in females primed only with EB. The present experiment employed three techniques to better understand what changes occur to DA receptors (DARs) in the mPOA under different hormonal profiles. Ovariectomized females were randomly assigned to one of three steroid treatment groups: EB + P (10 and 500 µg, respectively), EB + Oil, or the control (Oil + Oil), with hormone injections administered at 48 and 4 h prior to euthanizing. First, the number of neurons in the mPOA that contained D1R or D2R was assessed using immunohistochemistry. Second, the mPOA and two control areas (the prelimbic cortex and caudate putamen) were analysed for DAR protein levels using western blot, and DAR functional binding levels using autoradiography. Ovarian steroid hormones affected the two DAR subtypes in opposite ways in the mPOA. All three techniques supported previous behavioural findings that females primed with EB have a lower D1R : D2R ratio, and thus a D2R-mediated system, and females primed with EB + P have a higher D1R : D2R ratio, and thus a D1R-mediated system. This provides strong evidence for a DA-driven pathway of female sexual motivation, desire, and behaviour that is modified by different hormone priming regimens.

Interactions between glutamate, dopamine, and the neuronal signature of response inhibition in the human striatum.

Response inhibition is a basic mechanism in cognitive control and dysfunctional in major psychiatric disorders. The neuronal mechanisms are in part driven by dopamine in the striatum. Animal data suggest a regulatory role of glutamate on the level of the striatum. We used a trimodal imaging procedure of the human striatum including F18-DOPA positron emission tomography, proton magnetic resonance spectroscopy, and functional magnetic resonance imaging of a stop signal task. We investigated dopamine synthesis capacity and glutamate concentration in vivo and their relation to functional properties of response inhibition. A mediation analysis revealed a significant positive association between dopamine synthesis capacity and inhibition-related neural activity in the caudate nucleus. This relationship was significantly mediated by striatal glutamate concentration. Furthermore, stop signal reaction time was inversely related to striatal activity during inhibition. The data show, for the first time in humans, an interaction between dopamine, glutamate, and the neural signature of response inhibition in the striatum. This finding stresses the importance of the dopamine-glutamate interaction for behavior and may facilitate the understanding of psychiatric disorders characterized by impaired response inhibition.

Effect of Homocysteine on Voltage-Gated Sodium Channel Currents in Primary Cultured Rat Caudate Nucleus Neurons and Its Modulation by 2-Arachidonylglycerol.

Homocysteine (Hcy) is an important risk factor for Alzheimer's disease (AD) and other neurodegenerative diseases. Caudate nucleus (CN), the largest nucleus in the brain, is also implicated in many neurological disorders. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid, has been shown to exhibit neuroprotective effects from many stimuli in the central nervous system (CNS). Furthermore, it has been reported that voltage-gated sodium channels (VGSCs) are the common targets of many neuronal damages and drugs. However, it is still not clear whether VGSCs are involved in the neurotoxicity of Hcy and the neuroprotective effect of 2-AG in CN neurons. In the present study, whole-cell patch clamp recording was used to invest the action of Hcy on sodium currents in primary cultured rat CN neurons and its modulation by 2-AG. The results showed that in cultured CN neurons, pathological concentration of Hcy (100 µM) significantly increased the voltage-gated sodium currents (I(Na)) and produced a hyperpolarizing shift in the activation-voltage curve of I(Na). The further data demonstrated 2-AG is capable of suppressing elevation of Hcy-induced increase in I(Na) and hyperpolarizing shift of activation curves most partly through CB1 receptor-dependent way. Our study provides a better understanding of Hcy-associated neurological disorders and suggests the therapeutic potential for 2-AG for the treatment of these diseases.

A Corticostriatal Path Targeting Striosomes Controls Decision-Making under Conflict.

A striking neurochemical form of compartmentalization has been found in the striatum of humans and other species, dividing it into striosomes and matrix. The function of this organization has been unclear, but the anatomical connections of striosomes indicate their relation to emotion-related brain regions, including the medial prefrontal cortex. We capitalized on this fact by combining pathway-specific optogenetics and electrophysiology in behaving rats to search for selective functions of striosomes. We demonstrate that a medial prefronto-striosomal circuit is selectively active in and causally necessary for cost-benefit decision-making under approach-avoidance conflict conditions known to evoke anxiety in humans. We show that this circuit has unique dynamic properties likely reflecting striatal interneuron function. These findings demonstrate that cognitive and emotion-related functions are, like sensory-motor processing, subject to encoding within compartmentally organized representations in the forebrain and suggest that striosome-targeting corticostriatal circuits can underlie neural processing of decisions fundamental for survival.

Quantitative analysis of spiny neurons in the adult human caudate nucleus: can it confirm the current qualitative cell classification?

The caudate nucleus, as a part of the striatum (neostriatum or dorsal striatum), is involved in the control of cognitive, motor and limbic functions. The majority of the caudate nucleus cells are projection spiny neurons, whose activity is determined by excitatory inputs from the cortex, thalamus, globus pallidus and brainstem. A qualitative analysis of human caudate nucleus neurons involves the description of the structure and features of cells, and accordingly, their classification into an appropriate type. The aim of this study is to determine the justification of the current qualitative classification of spiny neurons in the precommissural head of the human caudate nucleus by quantifying morphological properties of neurons. After the qualitative analysis of microscopic images of the Golgi-impregnated caudate nucleus neurons, five morphological properties of cells were measured/quantified. In terms of the dendritic field area, caudate nucleus neurons were divided into two subgroups: small and large neurons. In our sample of 251 projection nerve cells, 58.17 % (146) were small and 41.83 % (105) were large neurons. These data show that suggested groups of spiny neurons in the human caudate nucleus differ in their morphology. Since the structure and function of cells are closely correlated, it is possible that these morphologically different types of neurons may represent different functional groups.

Projections from caudal ventrolateral prefrontal areas to brainstem preoculomotor structures and to Basal Ganglia and cerebellar oculomotor loops in the macaque.

The caudal part of the macaque ventrolateral prefrontal (VLPF) cortex hosts several distinct areas or fields--45B, 45A, 8r, caudal 46vc, and caudal 12r--connected to the frontal eye field (area 8/FEF). To assess whether these areas/fields also display subcortical projections possibly mediating a role in controlling oculomotor behavior, we examined their descending projections, based on anterograde tracer injections in each area/field, and compared them with those of area 8/FEF. All the studied areas/fields displayed projections to brainstem preoculomotor structures, precerebellar centers, and striatal sectors that are also targets of projections originating from area 8/FEF. Specifically, these projections involved: (1) the intermediate and superficial layers of the superior colliculus; (2) the mesencephalic and pontine reticular formation; (3) the dorsomedial and lateral pontine nuclei and the reticularis tegmenti pontis; and (4) the body of the caudate nucleus. Furthermore, area 45B projected also to the regions around the trochlear nucleus and to the raphe interpositus. The present data provide evidence for a role of the caudal VLPF areas/fields in controlling oculomotor behavior not only through their connections to area 8/FEF, but also in parallel through a direct access to preoculomotor brainstem structures and to the cerebellar and basal ganglia oculomotor loops.

Endocannabinoid 2-arachidonylglycerol protects primary cultured neurons against homocysteine-induced impairments in rat caudate nucleus through CB1 receptor.

Homocysteine (Hcy) is a high risk factor for Alzheimer's disease (AD). Caudate nucleus (CN), the major component of basal ganglia in the brain, is also involved in many neurological disorders. 2-Arachidonoylglycerol (2-AG), the true natural ligand for cannabinoid type-1 (CB1) receptors and the most abundant endogenous cannabinoid, has been shown to exhibit neuroprotective effects through its anti-inflammatory action from proinflammatory stimuli in the hippocampus and CN. However, it is still not well understood whether that 2-AG is also able to protect CN neurons from Hcy harmful insults. In the present work, we explored that 2-AG significantly protects CN neurons in culture against Hcy-induced response. 2-AG is capable of inhibiting elevation of Hcy-induced cyclooxygenase-2 expression associated with nuclear factor-kappaB/p38MAPK/ERK1/2 signaling pathway through CB1 receptors-dependent way in primary cultured CN neurons. Our study reveals the therapeutic potential for 2-AG for the treatment of neurodegenerative diseases, such as AD.

The distribution of transplanted human mesenchymal stem cells in the CNS of young Macaca fascicularis.

Mesenchymal stem cell (MSC)-based therapies have generated much hope and promise as a potential source of cells for cell-based therapeutic strategies in pediatric degenerative diseases. However, the distribution and migratory routes of MSCs are unknown. Here, real-time PCR and microscopy were used to observe the migration and distribution of labeled human MSCs (hMSCs) transplanted into the striatum of young Macaca fascicularis. Moreover, the differentiation of hMSCs was also detected using immunofluorescence. We found that hMSCs were mainly located near the injection site in the brain and in the anterior brain after 2 weeks. After 4 weeks, the hMSCs had dispersed and could be detected in each brain slice and were more uniformly distributed than after 2 weeks. The hMSCs showed a preference for migration towards blood vessels, which may be one of the migratory routes used by hMSCs. Additionally, hMSCs could be observed to give rise to NeuN- and GFAP-positive cells. Transplanted hMSCs also increased the expression levels of N-cadherin in the host brain tissue, which may be one factor that drives the migration and differentiation of hMSCs after transplantation. These results provide preclinical evidence that MSC-based therapies may represent an efficacious alternative to more conventional treatment regimens for a variety of pediatric neurologic disorders.

Cortical spreading depression modulates the caudate nucleus activity.

Cortical spreading depression (CSD) plays an important role in migraine with aura. The caudate nucleus has crucial functional interactions with brain regions likely to be important in migraine. The aim of the present in vitro study was to investigate the effect of CSD on the neuronal activity of the caudate. Intracellular recording was performed in the head of the caudate nucleus alongside of extracellular recording in Wistar rat somatosensory cortex. CSD was induced by local KCl injection. Changes in the membrane potentials of the caudate neurons began 1.2±0.2min after CSD. The neurons of the caudate nucleus depolarized first gradually and slightly then it depolarized abruptly at nearly the same point of time of the recovery of the cortical DC potential. Action potentials (APs) reappeared after the cortical DC shift returned to the baseline. Forty-five minutes after CSD, the caudate neurons showed lower frequency of APs and larger amplitude of depolarization prior to APs. The firing pattern of the caudate neurons evoked by injection of intracellular current pulses changed from slow adapting to fast adapting after CSD. Reduced neuronal activity in the caudate after CSD may be assumed to contribute to pain as well as changes in cognition and behavior in patients with migraine.