Deep electroacupuncture of neurogenic spots attenuates immobilization stress-induced acute hypertension in rats.

Background: Our previous studies proved that neurogenic inflammatory spots (or neurogenic spots) have the same physiological features as acupuncture points and that neurogenic spot stimulation generates therapeutic effects in various animal models. However, it is unclear how deeply the neurogenic spots should be stimulated to generate therapeutic effects. Methods: The effects of acupuncture at various needle depths below the neurogenic spot were examined in a rat immobilization stress-induced hypertension (IMH) model. Electroacupuncture was applied to a neurogenic spot at depths of 1, 2, or 3 mm using a concentric bipolar electrode. Results: Electrical stimulation of the neurogenic spot at a 3-mm depth most effectively lowered blood pressure compared with controls and stimulation at 1- and 2-mm depths, which was inhibited by pretreatment with a local anesthetic lidocaine. Electrical stimulation of the neurogenic spot or injection of substance P (SP) at a 3-mm depth significantly excited the rostral ventrolateral medulla (rVLM) compared with superficial stimulation. Electrical stimulation applied at a 3-mm depth on neurogenic spots dominantly caused c-fos expression from rVLM and ventrolateral periaqueductal gray (vlPAG) in IMH rats. Pretreatment with resiniferatoxin (RTX) injection into the neurogenic spot to ablate SP or calcitonin gene-related peptide (CGRP) prevented the effects of 3-mm neurogenic spot stimulation on blood pressure in IMH rats. Conversely, artificial injection of SP or CGRP generated anti-hypertensive effects in IMH rats. Conclusion: Our data suggest that neurogenic spot stimulation at a 3-mm depth generated anti-hypertensive effects through the local release of SP and CGRP and activation of rVLM and vlPAG.

Shared vs separate structural representations: Evidence from cumulative cross-language structural priming.

How do bilingual speakers represent the information that guides the assembly of words into sentences for their two languages? The shared-syntax account argues that bilinguals have a single, shared representation of the sentence structures that exist in both languages. Structural priming has been shown to be equal within and across languages, providing support for the shared-syntax account. However, equivalent levels of structural priming within and across languages could be observed even if structural representations are separate and connected, due to frequent switches between languages, which is a property of standard structural priming paradigms. Here, we investigated whether cumulative structural priming (i.e., structural priming across blocks rather than trial-by-trial), which does not involve frequent switches between languages, also shows equivalent levels of structural priming within- and cross-languages. Mixed results point towards a possibility that cumulative structural priming can be more persistent within- compared to cross-languages, suggesting a separate-and-connected account of bilingual structural representations. We discuss these results in terms of the current literature on bilingual structural representations and highlight the value of diversity in paradigms and less-studied languages.

Mediation of mPFC-LHb pathway in acupuncture inhibition of cocaine psychomotor activity.

The medial prefrontal cortex (mPFC) and the lateral habenula (LHb) play roles in drug addiction and cognitive functions. Our previous studies have suggested that acupuncture at Shenmen (HT7) points modulates mesolimbic reward system in order to suppress drug-induced addiction behaviours. To explore whether an mPFC-LHb circuit mediates the inhibitory effects of acupuncture on addictive behaviours, we examined the projection from mPFC to LHb, excitation of mPFC neurons during acupuncture stimulation, the effects of optogenetic modulation of mPFC-LHb on HT7 inhibition of cocaine-induced locomotion and the effect of mPFC lesion on HT7 inhibition of nucleus accumbens (NAc) dopamine release. Acupuncture was applied at bilateral HT7 points for 20 s, and locomotor activity was measured in male Sprague-Dawley rats. Although cocaine injection significantly increased locomotor activity, HT7 acupuncture suppressed the cocaine-induced locomotion. The inhibitory effect of HT7 on cocaine-enhanced locomotion was blocked by optogenetic silencing of the mPFC-LHb circuit. In vivo extracellular recordings showed that HT7 acupuncture evoked an increase in the action potentials of mPFC neurons. Optopatch experiment proved glutamatergic projections from mPFC to LHb. HT7 acupuncture suppressed NAc dopamine release following cocaine injection, which was blocked by electrolytic lesion of mPFC. These results suggest the mediation of mPFC-LHb circuit in the inhibitory effects of acupuncture on cocaine psychomotor activity in rats.

Mediation of lateral hypothalamus orexin input to lateral habenula in the inhibitory effects of mechanical stimulation on psychomotor responses induced by cocaine.

Introduction: The lateral hypothalamus (LH) plays an important physiological role in brain function and also plays an important role in substance abuse. The neuropeptides called orexin (or hypocretins) have been identified as being located exclusively in the cell bodies of the LH. Our previous studies have demonstrated that mechanical stimulation (MS) of the ulnar nerve produces strong inhibitory effects on cocaine addiction-like behaviors through activation of LH projection to the lateral habenula (LHb). Methods: Therefore, the present study hypothesized that ulnar MS would suppress the psychomotor responses induced by cocaine through the orexinergic LH-to-LHb pathway. Results: Ulnar MS attenuated cocaine enhancement of locomotor activity and 50-kHz ultrasonic vocalizations, which was prevented by antagonism of orexin-receptor type 2 (OX2R) in the LHb. Injection of orexin-A into the LHb reduced the cocaine-induced psychomotor responses. MS of the ulnar nerve excited LH orexinergic neurons. In addition, the excitation of LHb neurons by MS was blocked by the systemic administration of an OX2R antagonist. Discussion: These findings suggest that MS applied to the ulnar nerve recruits an orexinergic LH-to-LHb pathway to suppress the psychomotor responses induced by cocaine.

Activation of a hypothalamus-habenula circuit by mechanical stimulation inhibits cocaine addiction-like behaviors.

BACKGROUND: Mechanoreceptor activation modulates GABA neuron firing and dopamine (DA) release in the mesolimbic DA system, an area implicated in reward and substance abuse. The lateral habenula (LHb), the lateral hypothalamus (LH), and the mesolimbic DA system are not only reciprocally connected, but also involved in drug reward. We explored the effects of mechanical stimulation (MS) on cocaine addiction-like behaviors and the role of the LH-LHb circuit in the MS effects. MS was performed over ulnar nerve and the effects were evaluated by using drug seeking behaviors, optogenetics, chemogenetics, electrophysiology and immunohistochemistry. RESULTS: Mechanical stimulation attenuated locomotor activity in a nerve-dependent manner and 50-kHz ultrasonic vocalizations (USVs) and DA release in nucleus accumbens (NAc) following cocaine injection. The MS effects were ablated by electrolytic lesion or optogenetic inhibition of LHb. Optogenetic activation of LHb suppressed cocaine-enhanced 50 kHz USVs and locomotion. MS reversed cocaine suppression of neuronal activity of LHb. MS also inhibited cocaine-primed reinstatement of drug-seeking behavior, which was blocked by chemogenetic inhibition of an LH-LHb circuit. CONCLUSION: These findings suggest that peripheral mechanical stimulation activates LH-LHb pathways to attenuate cocaine-induced psychomotor responses and seeking behaviors.

Activation of a hypothalamus-habenula circuit by mechanical stimulation inhibits cocaine addiction-like behaviors

BACKGROUND: Mechanoreceptor activation modulates GABA neuron firing and dopamine (DA) release in the mesolimbic DA system, an area implicated in reward and substance abuse. The lateral habenula (LHb), the lateral hypothalamus (LH), and the mesolimbic DA system are not only reciprocally connected, but also involved in drug reward. We explored the effects of mechanical stimulation (MS) on cocaine addiction-like behaviors and the role of the LH-LHb circuit in the MS effects. MS was performed over ulnar nerve and the effects were evaluated by using drug seeking behaviors, optogenetics, chemogenetics, electrophysiology and immunohistochemistry. RESULTS: Mechanical stimulation attenuated locomotor activity in a nerve-dependent manner and 50-kHz ultrasonic vocalizations (USVs) and DA release in nucleus accumbens (NAc) following cocaine injection. The MS effects were ablated by electrolytic lesion or optogenetic inhibition of LHb. Optogenetic activation of LHb suppressed cocaine-enhanced 50 kHz USVs and locomotion. MS reversed cocaine suppression of neuronal activity of LHb. MS also inhibited cocaine-primed reinstatement of drug-seeking behavior, which was blocked by chemogenetic inhibition of an LH-LHb circuit. CONCLUSION: These findings suggest that peripheral mechanical stimulation activates LH-LHb pathways to attenuate cocaine-induced psychomotor responses and seeking behaviors.

An Increase in Peripheral Temperature following Cocaine Administration Is Mediated through Activation of Dopamine D2 Receptor in Rats.

Drug addiction has become a worldwide problem, affecting millions of people across the globe. While the majority of mechanistic studies on drug addiction have been focused on the central nervous system, including the mesolimbic dopamine system, the peripheral actions of drugs of abuse remain largely unknown. Our preliminary study found that the systemic injection of cocaine increased peripheral skin temperature. This led us to our present study, which investigated the mechanisms underlying the increase in peripheral temperature following cocaine injection. Male Sprague Dawley rats were anesthetized with pentobarbital sodium, and peripheral skin temperature measurements were taken using a thermocouple needle microprobe and an infrared thermal camera. Cocaine injection caused an acute rise in peripheral body temperature, but not core body temperature, about 10 min after injection, and the temperature increases were occluded by systemic injection of dopamine D2 receptor antagonist L741,626, but not D1 receptor antagonist SCH23390. In addition, systemic administration of bromocriptine, a dopamine D2 receptor agonist, significantly increased peripheral temperature. Infrared thermal imaging showed that the thermal increases following cocaine injection were predominantly in the distal areas of the forelimbs and hindlimbs, relative to core body temperature. Treatment with cocaine or bromocriptine decreased the size of skin blood vessels without affecting the expression of dopamine D2 receptors. These results suggest that increased peripheral temperature in skin following cocaine injection is associated with the activation of the dopamine D2 receptor.

Role of Lateral Hypothalamus in Acupuncture Inhibition of Cocaine Psychomotor Activity.

Acupuncture modulates the mesolimbic dopamine (DA) system; an area implicated in drug abuse. However, the mechanism by which peripheral sensory afferents, during acupuncture stimulation, modulate this system needs further investigation. The lateral hypothalamus (LH) has been implicated in reward processing and addictive behaviors. To investigate the role of the LH in mediating acupuncture effects, we evaluated the role of LH and spinohypothalamic neurons on cocaine-induced psychomotor activity and NAc DA release. Systemic injection of cocaine increased locomotor activity and 50 kHz ultrasonic vocalizations (USVs), which were attenuated by mechanical stimulation of needles inserted into HT7 but neither ST36 nor LI5. The acupuncture effects were blocked by chemical lesions of the LH or mimicked by activation of LH neurons. Single-unit extracellular recordings showed excitation of LH and spinohypothalamic neurons following acupuncture. Our results suggest that acupuncture recruits the LH to suppress the mesolimbic DA system and psychomotor responses following cocaine injection.

The role of substance P in acupuncture signal transduction and effects.

BACKGROUND: Acupuncture has been used to treat a wide variety of diseases, disorders, and conditions for more than 2500 years. While the anatomical structures of acupuncture points (or acupoints) are largely unknown, our previous studies have suggested that many acupoints can be identified as cutaneous neurogenic inflammatory spots (neurogenic spots or Neuro-Sps), arising from the release of neuropeptides from activated small diameter sensory afferents at topographically distinct body surfaces due to the convergence of visceral and somatic afferents. In turn, the neuropeptides released during neurogenic inflammation may play important roles in the effects of acupuncture as well as the formation of active acupoints. Thus, the present study has focused on the role of substance P (SP) in acupuncture signal transduction and effects. METHODS: Neuro-Sps were detected by using in vivo fluorescence imaging after intravenous injection of Evans blue dye (EBD) and compared with traditional acupoints. Stimulatory effects of the Neuro-Sps were examined in a rat model of immobilization-induced hypertension (IMH). The roles of increased SP in Neuro-Sps were also investigated by using immunohistochemistry, in vivo single-fiber peripheral nerve recordings, and in vivo midbrain extracellular recordings. RESULTS: Neurogenic inflammation quickly appeared at acupoints on the wrist and was fully developed within 15 min in IMH model. The Neuro-Sps showed an increased release of SP from afferent nerve terminals. Mechanical stimulation of these Neuro-Sps increased cell excitability in the midbrain (rostral ventrolateral medulla) and alleviated the development of hypertension, which was blocked by the local injection of the SP receptor antagonist CP-99994 into Neuro-Sps prior to acupuncture and mimicked by the local injection of capsaicin. Single fiber recordings of peripheral nerves showed that increased SP into the Neuro-Sps elevated the sensitivity of A- and C-fibers in response to acupuncture stimulation. In addition, the discharge rates of spinal wide dynamic response (WDR) neurons significantly increased following SP or acupuncture treatment in Neuro-Sps in normal rats, but decreased following the injection of CP-99994 into Neuro-Sps in IMH rats. CONCLUSIONS: Our findings suggest that SP released during neurogenic inflammation enhances the responses of sensory afferents to the needling of acupoints and triggers acupuncture signaling to generate acupuncture effects.

Minimal Overlap in Language Control Across Production And Comprehension: Evidence from Read-Aloud Versus Eye-Tracking Tasks.

Bilinguals are remarkable at language control-switching between languages only when they want. However, language control in production can involve switch costs. That is, switching to another language takes longer than staying in the same language. Moreover, bilinguals sometimes produce language intrusion errors, mistakenly producing words in an unintended language (e.g., Spanish-English bilinguals saying "pero" instead of "but"). Switch costs are also found in comprehension. For example, reading times are longer when bilinguals read sentences with language switches compared to sentences with no language switches. Given that both production and comprehension involve switch costs, some language-control mechanisms might be shared across modalities. To test this, we compared language switch costs found in eye-movement measures during silent sentence reading (comprehension) and intrusion errors produced when reading aloud switched words in mixed-language paragraphs (production). Bilinguals who made more intrusion errors during the read-aloud task did not show different switch cost patterns in most measures in the silent-reading task, except on skipping rates. We suggest that language switching is mostly controlled by separate, modality-specific processes in production and comprehension, although some points of overlap might indicate the role of domain general control and how it can influence individual differences in bilingual language control.

Noble metal sensitized invasive porous bioelectrodes: advanced medical device for enhanced neuronal activity and chronic alcohol treatment.

Invasive bioelectrodes are widely used as an effective treatment for several acute and chronic diseases. In earlier work using high surface area invasive porous bioelectrodes evaluated in an animal model of alcoholism withdrawal, we demonstrated significantly improved electrophysiological and behavioral responses. In this study, we further modify the surface of these invasive porous bioelectrodes with noble metal (Ag, Au, Pt) nanoparticles. Compared to both conventional and porous bioelectrodes, noble metal sensitized invasive porous bioelectrodes show markedly increased low threshold (LT) and wide dynamic range (WDR) neuronal activity. In particular, Pt-sensitized invasive porous bioelectrodes show the highest WDR neuronal activity only upon insertion. In addition, Ag-sensitized invasive porous bioelectrodes, whose surface area is about 37 times greater than that of conventional bioelectrodes, show improved electrochemical properties with higher LT and WDR neuronal activity when stimulated. In an animal model of chronic alcoholism, using normal and alcohol-treated Sprague-Dawley (SD) rats evaluated with the elevated plus maze (EPM) test, the Ag-sensitized invasive porous bioelectrodes show about 20% higher open arms time. These results suggest that these noble metal-sensitized invasive bioelectrodes may offer improved therapeutic outcomes for the treatment of chronic alcoholism, and given these enhanced electrophysiological properties, for other conditions as well.