Connexin-36-positive gap junctions in ventral tegmental area GABA neurons sustain opiate dependence.

Drug dependence is characterized by a switch in motivation wherein a positively reinforcing substance can become negatively reinforcing. Put differently, drug use can transform from a form of pleasure-seeking to a form of relief-seeking. Ventral tegmental area (VTA) GABA neurons form an anatomical point of divergence between two double dissociable pathways that have been shown to be functionally implicated and necessary for these respective motivations to seek drugs. The tegmental pedunculopontine nucleus (TPP) is necessary for opiate conditioned place preferences (CPP) in previously drug-naïve rats and mice, whereas dopaminergic (DA) transmission in the nucleus accumbens (NAc) is necessary for opiate CPP in opiate-dependent and withdrawn (ODW) rats and mice. Here, we show that this switch in functional anatomy is contingent upon the gap junction-forming protein, connexin-36 (Cx36), in VTA GABA neurons. Intra-VTA infusions of the Cx36 blocker, mefloquine, in ODW rats resulted in a reversion to a drug-naïve-like state wherein the TPP was necessary for opiate CPP and where opiate withdrawal aversions were lost. Consistent with these data, conditional knockout mice lacking Cx36 in GABA neurons (GAD65-Cre;Cx36 fl(CFP)/fl(CFP)) exhibited a perpetual drug-naïve-like state wherein opiate CPP was always DA independent, and opiate withdrawal aversions were absent even in mice subjected to an opiate dependence and withdrawal induction protocol. Further, viral-mediated rescue of Cx36 in VTA GABA neurons was sufficient to restore their susceptibility to an ODW state wherein opiate CPP was DA dependent. Our findings reveal a functional role for VTA gap junctions that has eluded prevailing circuit models of addiction.

Differential modulation of thermal preference after sensitization by optogenetic or pharmacological activation of heat-sensitive nociceptors.

Common approaches to studying mechanisms of chronic pain and sensory changes in pre-clinical animal models involve measurement of acute, reflexive withdrawal responses evoked by noxious stimuli. These methods typically do not capture more subtle changes in sensory processing nor report on the consequent behavioral changes. In addition, data collection and analysis protocols are often labour-intensive and require direct investigator interactions, potentially introducing bias. In this study, we develop and characterize a low-cost, easily assembled behavioral assay that yields self-reported temperature preference from mice that is responsive to peripheral sensitization. This system uses a partially automated and freely available analysis pipeline to streamline the data collection process and enable objective analysis. We found that after intraplantar administration of the TrpV1 agonist, capsaicin, mice preferred to stay in cooler temperatures than saline injected mice. We further observed that gabapentin, a non-opioid analgesic commonly prescribed to treat chronic pain, reversed this aversion to higher temperatures. In contrast, optogenetic activation of the central terminals of TrpV1+ primary afferents via in vivo spinal light delivery did not induce a similar change in thermal preference, indicating a possible role for peripheral nociceptor activity in the modulation of temperature preference. We conclude that this easily produced and robust sensory assay provides an alternative approach to investigate the contribution of central and peripheral mechanisms of sensory processing that does not rely on reflexive responses evoked by noxious stimuli.

Pharmacists' knowledge, experiences and perceptions of treatments for attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that begins in childhood and often persists into adulthood. ADHD increases the risk of various negative impacts, and pharmacists are well positioned to address these issues in the community. OBJECTIVES: This survey study aims to first identify pharmacists' ADHD knowledge gaps and experience with ADHD management and to second assess their preferences for continuing education and their experience with sleep-related issues in ADHD. METHODS: A survey was sent to Part A Ontario pharmacists with active licenses who opted in to receive research-related emails (n = 6022). Descriptive statistics were used to analyze survey data, while free-form answers were pooled and evaluated for common themes and trends. RESULTS: A total of 238 complete responses were received. The average self-reported ADHD knowledge was 5.8 ± 1.96 on a 10-point scale. There was no correlation between the number of years of practice as a pharmacist, the number of working hours per week or the location of practice on pharmacists' self-reported knowledge scores. There was a significant difference in self-reported knowledge of ADHD between pharmacists who were not aware of the Canadian ADHD Resource Alliance (CADDRA) guidelines (5.1 ± 2.1) and those who refer to it for standard of care (7.1 ± 1.5). Almost all pharmacists (95%) indicated they could benefit from additional ADHD education, with a strong preference for "online continuing education modules" (81%). The majority of responders considered psychostimulant ADHD medication as the major possible contributor to sleep disturbances (47%) in ADHD, highlighting a need for further education on the inconclusive link between ADHD medication effects on sleep. CONCLUSION: The study results raise the concern that pharmacists may require additional ADHD education but also show the lack of awareness of available resources, such as the CADDRA guidelines. Can Pharm J (Ott) 2021;154:xx-xx.

Dexmedetomidine Prevents Excessive γ-Aminobutyric Acid Type A Receptor Function after Anesthesia.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Postoperative delirium is associated with poor long-term outcomes and increased mortality. General anesthetic drugs may contribute to delirium because they increase cell-surface expression and function of α5 subunit-containing γ-aminobutyric acid type A receptors, an effect that persists long after the drugs have been eliminated. Dexmedetomidine, an α2 adrenergic receptor agonist, prevents delirium in patients and reduces cognitive deficits in animals. Thus, it was postulated that dexmedetomidine prevents excessive function of α5 γ-aminobutyric acid type A receptors. METHODS: Injectable (etomidate) and inhaled (sevoflurane) anesthetic drugs were studied using cultured murine hippocampal neurons, cultured murine and human cortical astrocytes, and ex vivo murine hippocampal slices. γ-Aminobutyric acid type A receptor function and cell-signaling pathways were studied using electrophysiologic and biochemical methods. Memory and problem-solving behaviors were also studied. RESULTS: The etomidate-induced sustained increase in α5 γ-aminobutyric acid type A receptor cell-surface expression was reduced by dexmedetomidine (mean ± SD, etomidate: 146.4 ± 51.6% vs. etomidate + dexmedetomidine: 118.4 ± 39.1% of control, n = 8 each). Dexmedetomidine also reduced the persistent increase in tonic inhibitory current in hippocampal neurons (etomidate: 1.44 ± 0.33 pA/pF, n = 10; etomidate + dexmedetomidine: 1.01 ± 0.45 pA/pF, n = 9). Similarly, dexmedetomidine prevented a sevoflurane-induced increase in the tonic current. Dexmedetomidine stimulated astrocytes to release brain-derived neurotrophic factor, which acted as a paracrine factor to reduce excessive α5 γ-aminobutyric acid type A receptor function in neurons. Finally, dexmedetomidine attenuated memory and problem-solving deficits after anesthesia. CONCLUSIONS: Dexmedetomidine prevented excessive α5 γ-aminobutyric acid type A receptor function after anesthesia. This novel α2 adrenergic receptor- and brain-derived neurotrophic factor-dependent pathway may be targeted to prevent delirium.

α5GABAA Receptors Mediate Tonic Inhibition in the Spinal Cord Dorsal Horn and Contribute to the Resolution Of Hyperalgesia.

Neuronal inhibition mediated by GABAA receptors constrains nociceptive processing in the spinal cord, and loss of GABAergic inhibition can produce allodynia and hyperalgesia. Extrasynaptic α5 subunit-containing GABAA receptors (α5GABAA Rs) generate a tonic conductance that inhibits neuronal activity and constrains learning and memory; however, it is unclear whether α5GABAA Rs similarly generate a tonic conductance in the spinal cord dorsal horn to constrain nociception. We assessed the distribution of α5GABAA Rs in the spinal cord dorsal horn by immunohistochemical analysis, and the activity and function of α5GABAA Rs in neurons of the superficial dorsal horn using electrophysiological and behavioral approaches in male, null-mutant mice lacking the GABAA R α5 subunit (Gabra5-/-) and wild-type mice (WT). The expression of α5GABAA Rs in the superficial dorsal horn followed a laminar pattern of distribution, with a higher expression in lamina II than lamina I. Similarly, the tonic GABAA current in lamina II neurons had a larger contribution from α5GABAA Rs than in lamina I, with no significant contribution of these receptors to synaptic GABAA current. In behavioural tests, WT and Gabra5-/- mice exhibited similar acute thermal and mechanical nociception, and similar mechanical sensitization immediately following intraplantar capsaicin or Complete Freund's Adjuvant (CFA). However, Gabra5-/- mice showed prolonged recovery from sensitization in these models, and increased responses in the late phase of the formalin test. Overall, our data suggest that tonically-active α5GABAA Rs in the spinal cord dorsal horn accelerate the resolution of hyperalgesia and may therefore serve as a novel therapeutic target to promote recovery from pathological pain. © 2016 Wiley Periodicals, Inc.

Epidural optogenetics for controlled analgesia.

BACKGROUND: Optogenetic tools enable cell selective and temporally precise control of neuronal activity; yet, difficulties in delivering sufficient light to the spinal cord of freely behaving animals have hampered the use of spinal optogenetic approaches to produce analgesia. We describe an epidural optic fiber designed for chronic spinal optogenetics that enables the precise delivery of light at multiple wavelengths to the spinal cord dorsal horn and sensory afferents. RESULTS: The epidural delivery of light enabled the optogenetic modulation of nociceptive processes at the spinal level. The acute and repeated activation of channelrhodopsin-2 expressing nociceptive afferents produced robust nocifensive behavior and mechanical sensitization in freely behaving mice, respectively. The optogenetic inhibition of GABAergic interneurons in the spinal cord dorsal horn through the activation of archaerhodopsin also produced a transient, but selective induction of mechanical hypersensitivity. Finally, we demonstrate the capacity of optogenetics to produce analgesia in freely behaving mice through the inhibition of nociceptive afferents via archaerhodopsin. CONCLUSION: Epidural optogenetics provides a robust and powerful solution for activation of both excitatory and inhibitory opsins in sensory processing pathways. Our results demonstrate the potential of spinal optogenetics to modulate sensory behavior and produce analgesia in freely behaving animals.

Remote optogenetic activation and sensitization of pain pathways in freely moving mice.

We report a novel model in which remote activation of peripheral nociceptive pathways in transgenic mice is achieved optogenetically, without any external noxious stimulus or injury. Taking advantage of a binary genetic approach, we selectively targeted Nav1.8(+) sensory neurons for conditional expression of channelrhodopsin-2 (ChR2) channels. Acute blue light illumination of the skin produced robust nocifensive behaviors, evoked by the remote stimulation of both peptidergic and nonpeptidergic nociceptive fibers as indicated by c-Fos labeling in laminae I and II of the dorsal horn of the spinal cord. A non-nociceptive component also contributes to the observed behaviors, as shown by c-Fos expression in lamina III of the dorsal horn and the expression of ChR2-EYFP in a subpopulation of large-diameter Nav1.8(+) dorsal root ganglion neurons. Selective activation of Nav1.8(+) afferents in vivo induced central sensitization and conditioned place aversion, thus providing a novel paradigm to investigate plasticity in the pain circuitry. Long-term potentiation was similarly evoked by light activation of the same afferents in isolated spinal cord preparations. These findings demonstrate, for the first time, the optical control of nociception and central sensitization in behaving mammals and enables selective activation of the same class of afferents in both in vivo and ex vivo preparations. Our results provide a proof-of-concept demonstration that optical dissection of the contribution of specific classes of afferents to central sensitization is possible. The high spatiotemporal precision offered by this non-invasive model will facilitate drug development and target validation for pain therapeutics.

A simplified up-down method (SUDO) for measuring mechanical nociception in rodents using von Frey filaments.

BACKGROUND: The measurement of mechanosensitivity is a key method for the study of pain in animal models. This is often accomplished with the use of von Frey filaments in an up-down testing paradigm. The up-down method described by Chaplan et al. (J Neurosci Methods 53:55-63, 1994) for mechanosensitivity testing in rodents remains one of the most widely used methods for measuring pain in animals. However, this method results in animals receiving a varying number of stimuli, which may lead to animals in different groups receiving different testing experiences that influences their later responses. To standardize the measurement of mechanosensitivity we developed a simplified up-down method (SUDO) for estimating paw withdrawal threshold (PWT) with von Frey filaments that uses a constant number of five stimuli per test. We further refined the PWT calculation to allow the estimation of PWT directly from the behavioral response to the fifth stimulus, omitting the need for look-up tables. RESULTS: The PWT estimates derived using SUDO strongly correlated (r > 0.96) with the PWT estimates determined with the conventional up-down method of Chaplan et al., and this correlation remained very strong across different levels of tester experience, different experimental conditions, and in tests from both mice and rats. The two testing methods also produced similar PWT estimates in prospective behavioral tests of mice at baseline and after induction of hyperalgesia by intraplantar capsaicin or complete Freund's adjuvant. CONCLUSION: SUDO thus offers an accurate, fast and user-friendly replacement for the widely used up-down method of Chaplan et al.

Virtually simulated interpersonal touch negatively affects perceived closeness and social affiliation to an avatar partner.

Interpersonal touch is an essential component of human non-verbal communication, facilitating social affiliation and bonding. With the widespread use of digital interfaces and online platforms in all realms of human interactions, there are fewer opportunities for communicating through touch. Popular online platforms that virtually simulate human interactions rely primarily on visual and auditory modalities, providing limited or no capacity for the exchange of tactile cues. Previous studies of virtual interactions have explored the simulation of social touch using haptic devices, but little is known about how the visual representation of interpersonal touch is perceived and integrated into a virtual social experience. In two studies we examined how the exchange of virtual touch mediated by simulated 3-dimensional human characters, or avatars, within an online virtual environment influenced affiliation towards an unfamiliar interaction partner. Surprisingly, the exchange of virtual touch negatively affected the perceived closeness and affiliation to the partner and the social evaluation of the interaction but did not affect the level of physiological arousal during the interaction. These results indicate that the visual representation of social touch is sufficient to virtually communicate touch-related cues that impact social affiliation, but the influence of touch may be dependent on the interaction context.

The State of Synthetic Cannabinoid Medications for the Treatment of Pain.

Synthetic cannabinoids are compounds made in the laboratory to structurally and functionally mimic phytocannabinoids from the Cannabis sativa L. plant, including delta-9-tetrahydrocannabinol (THC). Synthetic cannabinoids (SCs) can signal via the classical endogenous cannabinoid system (ECS) and the greater endocannabidiome network, highlighting their signalling complexity and far-reaching effects. Dronabinol and nabilone, which mimic THC signalling, have been approved by the Food and Drug Administration (FDA) for treating nausea associated with cancer chemotherapy and/or acquired immunodeficiency syndrome (AIDS). However, there is ongoing interest in these two drugs as potential analgesics for a variety of other clinical conditions, including neuropathic pain, spasticity-related pain, and nociplastic pain syndromes including fibromyalgia, osteoarthritis, and postoperative pain, among others. In this review, we highlight the signalling mechanisms of FDA-approved synthetic cannabinoids, discuss key clinical trials that investigate their analgesic potential, and illustrate challenges faced when bringing synthetic cannabinoids to the clinic.

Nociceptor activity induces nonionotropic NMDA receptor signaling to enable spinal reconsolidation and reverse pathological pain.

Chronic, pathological pain is a highly debilitating condition that can arise and be maintained through central sensitization. Central sensitization shares mechanistic and phenotypic parallels with memory formation. In a sensory model of memory reconsolidation, plastic changes underlying pain hypersensitivity can be dynamically regulated and reversed following the reactivation of sensitized sensory pathways. However, the mechanisms by which synaptic reactivation induces destabilization of the spinal "pain engram" are unclear. We identified nonionotropic N-methyl-d-aspartate receptor (NI-NMDAR) signaling as necessary and sufficient for the reactive destabilization of dorsal horn long-term potentiation and the reversal of mechanical sensitization associated with central sensitization. NI-NMDAR signaling engaged directly or through the reactivation of sensitized sensory networks was associated with the degradation of excitatory postsynaptic proteins. Our findings identify NI-NMDAR signaling as a putative synaptic mechanism by which engrams are destabilized in reconsolidation and as a potential means of treating underlying causes of chronic pain.

Brain-Penetrating and Disease Site-Targeting Manganese Dioxide-Polymer-Lipid Hybrid Nanoparticles Remodel Microenvironment of Alzheimer's Disease by Regulating Multiple Pathological Pathways.

Finding effective disease-modifying treatment for Alzheimer's disease remains challenging due to an array of factors contributing to the loss of neural function. The current study demonstrates a new strategy, using multitargeted bioactive nanoparticles to modify the brain microenvironment to achieve therapeutic benefits in a well-characterized mouse model of Alzheimer's disease. The application of brain-penetrating manganese dioxide nanoparticles significantly reduces hypoxia, neuroinflammation, and oxidative stress; ultimately reducing levels of amyloid ß plaques within the neocortex. Analyses of molecular biomarkers and magnetic resonance imaging-based functional studies indicate that these effects improve microvessel integrity, cerebral blood flow, and cerebral lymphatic clearance of amyloid ß. These changes collectively shift the brain microenvironment toward conditions more favorable to continued neural function as demonstrated by improved cognitive function following treatment. Such multimodal disease-modifying treatment may bridge critical gaps in the therapeutic treatment of neurodegenerative disease.

The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis.

BACKGROUND: Many clinical trials have demonstrated the effectiveness of gabapentin and pregabalin administration in the perioperative period as an adjunct to reduce acute postoperative pain. However, very few clinical trials have examined the use of gabapentin and pregabalin for the prevention of chronic postsurgical pain (CPSP). We (1) systematically reviewed the published literature pertaining to the prevention of CPSP (≥ 2 months after surgery) after perioperative administration of gabapentin and pregabalin and (2) performed a meta-analysis using studies that report sufficient data. A search of electronic databases (Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, IPA, and CINAHL) for relevant English-language trials to June 2011 was conducted. METHODS: The following inclusion criteria for identified clinical trials were used for entry into the present systematic review: randomization; double-blind assessments of pain and analgesic use; report of pain using a reliable and valid measure; report of analgesic consumption; and an absence of design flaws, methodological problems or confounders that render interpretation of the results ambiguous. Trials that did not fit the definition of preventive analgesia and did not assess chronic pain at 2 or more months after surgery were excluded. RESULTS: The database search yielded 474 citations. Eleven studies met the inclusion criteria. Of the 11 trials, 8 studied gabapentin, 4 of which (i.e., 50%) found that perioperative administration of gabapentin decreased the incidence of chronic pain more than 2 months after surgery. The 3 trials that used pregabalin demonstrated a significant reduction in the incidence of CPSP, and 2 of the 3 trials also found an improvement in postsurgical patient function. Eight studies were included in a meta-analysis, 6 of the gabapentin trials demonstrated a moderate-to-large reduction in the development of CPSP (pooled odds ratio [OR] 0.52; 95% confidence interval [CI], 0.27 to 0.98; P = 0.04), and the 2 pregabalin trials found a very large reduction in the development of CPSP (pooled OR 0.09; 95% CI, 0.02 to 0.79; P = 0.007). CONCLUSIONS: The present review supports the view that perioperative administration of gabapentin and pregabalin are effective in reducing the incidence of CPSP. Better-designed and appropriately powered clinical trials are needed to confirm these early findings.

Identifying genetic determinants of inflammatory pain in mice using a large-scale gene-targeted screen.

ABSTRACT: Identifying the genetic determinants of pain is a scientific imperative given the magnitude of the global health burden that pain causes. Here, we report a genetic screen for nociception, performed under the auspices of the International Mouse Phenotyping Consortium. A biased set of 110 single-gene knockout mouse strains was screened for 1 or more nociception and hypersensitivity assays, including chemical nociception (formalin) and mechanical and thermal nociception (von Frey filaments and Hargreaves tests, respectively), with or without an inflammatory agent (complete Freund's adjuvant). We identified 13 single-gene knockout strains with altered nocifensive behavior in 1 or more assays. All these novel mouse models are openly available to the scientific community to study gene function. Two of the 13 genes (Gria1 and Htr3a) have been previously reported with nociception-related phenotypes in genetically engineered mouse strains and represent useful benchmarking standards. One of the 13 genes (Cnrip1) is known from human studies to play a role in pain modulation and the knockout mouse reported herein can be used to explore this function further. The remaining 10 genes (Abhd13, Alg6, BC048562, Cgnl1, Cp, Mmp16, Oxa1l, Tecpr2, Trim14, and Trim2) reveal novel pathways involved in nociception and may provide new knowledge to better understand genetic mechanisms of inflammatory pain and to serve as models for therapeutic target validation and drug development.

Physical Contact Promotes the Development of Emotional Contagion Between Mice.

The establishment and maintenance of strong affiliative relationships is fundamental for group cohesion and crucial for overall individual well-being. Empathy is considered a critical process for promoting attachment and the long-term stability of social bonds. However, it is unclear how different modalities of social communication contribute to the development of empathy. Physical contact between individuals, such as gentle touching, is a highly salient form of social communication. Despite mounting evidence that touch may be crucial for promoting social bonds, the role of touch in the development of empathy is currently not well understood. Animal models have become a powerful tool for the experimental manipulation and examination of empathy related behaviors such as emotional contagion. Here, we use the Tube Co-Occupancy Test (TCOT) to promote voluntary physical contact between mice and examine whether social, physical contact promotes emotional contagion of pain between mice. We found that repeated exposure to TCOT promoted the development of emotional contagion between mice. However, preventing physical contact in the TCOT assay also prevented the development of emotional contagion of pain. These results demonstrate that voluntary physical contact is a critical component in the formation of social bonding and emotional contagion in mice.

The T-type calcium channel antagonist, Z944, reduces spinal excitability and pain hypersensitivity.

BACKGROUND AND PURPOSE: T-type voltage-gated calcium channels are an emerging therapeutic target for neurological disorders including epilepsy and pain. Inhibition of T-type channels reduces the excitability of peripheral nociceptive sensory neurons and reverses pain hypersensitivity in male rodent pain models. However, administration of peripherally restricted T-type antagonists failed to show efficacy in multiple clinical and preclinical pain trials, suggesting that inhibition of peripheral T-type channels alone may be insufficient for pain relief. EXPERIMENTAL APPROACH: We utilized the selective and CNS-penetrant T-type channel antagonist, Z944, in electrophysiological, calcium imaging and behavioural paradigms to determine its effect on lamina I neuron excitability and inflammatory pain behaviours. KEY RESULTS: Voltage-clamp recordings from lamina I spinal neurons of adult rats revealed that approximately 80% of neurons possess a low threshold T-type current, which was blocked by Z944. Due to this highly prevalent T-type current, Z944 potently blocked action-potential evoked somatic and dendritic calcium transients in lamina I neurons. Moreover, application of Z944 to spinal cord slices attenuated action potential firing rates in over half of laminae I/II neurons. Finally, we found that intraperitoneal injection of Z944 (1-10 mg·kg-1 ) dose-dependently reversed mechanical allodynia in the complete Freund's adjuvant model of persistent inflammatory pain, with a similar magnitude and time course of analgesic effects between male and female rats. CONCLUSION AND IMPLICATIONS: T-type calcium channels critically shape the excitability of lamina I pain processing neurons and inhibition of these channels by the clinical stage antagonist Z944 potently reverses pain hypersensitivity across sexes.

Cage-lid hanging behavior as a translationally relevant measure of pain in mice.

ABSTRACT: The development of new analgesic drugs has been hampered by the inability to translate preclinical findings to humans. This failure is due in part to the weak connection between commonly used pain outcome measures in rodents and the clinical symptoms of chronic pain. Most rodent studies rely on the use of experimenter-evoked measures of pain and assess behavior under ethologically unnatural conditions, which limits the translational potential of preclinical research. Here, we addressed this problem by conducting an unbiased, prospective study of behavioral changes in mice within a natural homecage environment using conventional preclinical pain assays. Unexpectedly, we observed that cage-lid hanging, a species-specific elective behavior, was the only homecage behavior reliably impacted by pain assays. Noxious stimuli reduced hanging behavior in an intensity-dependent manner, and the reduction in hanging could be restored by analgesics. Finally, we developed an automated approach to assess hanging behavior. Collectively, our results indicate that the depression of hanging behavior is a novel, ethologically valid, and translationally relevant pain outcome measure in mice that could facilitate the study of pain and analgesic development.

Insights Into Spinal Dorsal Horn Circuit Function and Dysfunction Using Optical Approaches.

Somatosensation encompasses a variety of essential modalities including touch, pressure, proprioception, temperature, pain, and itch. These peripheral sensations are crucial for all types of behaviors, ranging from social interaction to danger avoidance. Somatosensory information is transmitted from primary afferent fibers in the periphery into the central nervous system via the dorsal horn of the spinal cord. The dorsal horn functions as an intermediary processing center for this information, comprising a complex network of excitatory and inhibitory interneurons as well as projection neurons that transmit the processed somatosensory information from the spinal cord to the brain. It is now known that there can be dysfunction within this spinal cord circuitry in pathological pain conditions and that these perturbations contribute to the development and maintenance of pathological pain. However, the complex and heterogeneous network of the spinal dorsal horn has hampered efforts to further elucidate its role in somatosensory processing. Emerging optical techniques promise to illuminate the underlying organization and function of the dorsal horn and provide insights into the role of spinal cord sensory processing in shaping the behavioral response to somatosensory input that we ultimately observe. This review article will focus on recent advances in optogenetics and fluorescence imaging techniques in the spinal cord, encompassing findings from both in vivo and in vitro preparations. We will also discuss the current limitations and difficulties of employing these techniques to interrogate the spinal cord and current practices and approaches to overcome these challenges.

Anisotropic light scattering from myelinated axons in the spinal cord.

Optogenetics has become an integral tool for studying and dissecting the neural circuitries of the brain using optical control. Recently, it has also begun to be used in the investigation of the spinal cord and peripheral nervous system. However, information on these regions' optical properties is sparse. Moreover, there is a lack of data on the dependence of light propagation with respect to neural tissue organization and orientation. This information is important for effective simulations and optogenetic planning, particularly in the spinal cord where the myelinated axons are highly organized. To this end, we report experimental measurements for the scattering coefficient, validated with three different methods in both the longitudinal and radial directions of multiple mammalian spinal cords. In our analysis, we find that there is indeed a directional dependence of photon propagation when interacting with organized myelinated axons. Specifically, light propagating perpendicular to myelinated axons in the white matter of the spinal cord produced a measured reduced scattering coefficient ( µ s ' ) of 3.52 ± 0.1 mm - 1 , and light that was propagated along the myelinated axons in the white matter produced a measured µ s ' of 1.57 ± 0.03 mm - 1 , across the various species considered. This 50% decrease in scattering power along the myelinated axons is observed with three different measurement strategies (integrating spheres, observed transmittance, and punch-through method). Furthermore, this directional dependence in scattering power and overall light attenuation did not occur in the gray matter regions where the myelin organization is nearly random. The acquired information will be integral in preparing future light-transport simulations and in overall optogenetic planning in both the spinal cord and the brain.

The physiological properties and therapeutic potential of alpha5-GABAA receptors.

The notion that drug treatments can improve memory performance has moved from the realm of science fiction to that of serious investigation. A popular working hypothesis is that cognition can be improved by altering the balance between excitatory and inhibitory neurotransmission. This review focuses on the unique physiological and pharmacological properties of GABA(A)Rs [GABA (gamma-aminobutyric acid) subtype A receptors] that contain the alpha(5) subunit (alpha(5)-GABA(A)R), as these receptors serve as candidate targets for memory-enhancing drugs.