Excitatory Neuronal Responses Research Articles

All‐Optically Triggered In‐Sensor Collision Detection and Warning Based on 2D Complementary Material Devices

AbstractPrecise and timely collision detection and warning are essential to ensure the safety of autonomous driving. However, existing collision detection systems based on image sensors and radars are prone to misjudgment in adverse environments such as darkness or rain. The lobula giant movement detector (LGMD) neuron found in locusts achieves potential collision detection in unpredictable environments without the need for object recognition algorithms. Existing artificial collision detectors inspired by LGMD suffer from complex device structures and sophisticated operating modes. Here, an LGMD‐inspired all‐optically triggered in‐sensor collision detector is presented by 2D complementary material devices (2D‐CMDs) composed of n‐type molybdenum disulfide (MoS2) and p‐type platinum diselenide (PtSe2) connected in series. The proposed 2D‐CMDs couple the positive photoconductivity of MoS2 and negative photoconductivity of PtSe2 in response to looming light, successfully mimicking the antagonism of excitatory and inhibitory responses in LGMD neurons to generate a nonmonotonic escape response. The 2D‐CMDs exhibit a simple device structure and all‐optically controlled operation mode, consuming only 1 nJ of energy for each collision detection. Furthermore, in‐sensor real‐time collision warning is realized by employing a Recurrent Neural Network (RNN) to predict alarm time based on the escape response of the proposed 2D‐CMDs.

Cortical cellular encoding of thermotactile integration

Recent evidence suggests that primary sensory cortical regions play a role in the integration of information from multiple sensory modalities. How primary cortical neurons integrate different sources of sensory information is unclear, partly because non-primary sensory input to a cortical sensory region is often weak or modulatory. To address this question, we take advantage of the robust representation of thermal (cooling) and tactile stimuli in mouse forelimb primary somatosensory cortex (fS1). Using a thermotactile detection task, we show that the perception of threshold-level cool or tactile information is enhanced when they are presented simultaneously, compared with presentation alone. To investigate the cortical cellular correlates of thermotactile integration, we performed invivo extracellular recordings from fS1 in awake resting and anesthetized mice during unimodal and bimodal stimulation of the forepaw. Unimodal stimulation evoked thermal- or tactile- specific excitatory and inhibitory responses of fS1 neurons. The most prominent features of combined thermotactile stimulation are the recruitment of unimodally silent fS1 neurons, non-linear integration features, and response dynamics that favor longer response durations with additional spikes. Together, we identify quantitative and qualitative changes in cortical encoding that may underlie the improvement in perception of thermotactile surfaces during haptic exploration.

Menthacarin treatment attenuates nociception in models of visceral hypersensitivity.

Chronic visceral hypersensitivity is closely associated with irritable bowel syndrome (IBS), a very common disorder which significantly impairs quality of life, characterized by abdominal pain, and distension. Imaging studies have found that IBS patients show higher metabolic activities and functional differences from normal controls in the anterior cingulate cortex (ACC), in response to visceral pain stimulation. Non-clinical data and clinical data suggest that medicinal products containing essential oils such as peppermint or caraway oil exert beneficial effects on IBS symptoms. We assessed acute and long-term treatment effects of a mixture of peppermint and caraway essential oils (Menthacarin) on brain electrophysiological markers of gut pain sensitivity in two rat models of visceral hypersensitivity. Chronic administration of corticosteroids and acute repeated mechanical hyperstimulation under anesthesia induced hyperalgesia and hypersensitivity, characterized by an increase in electrophysiological excitatory responses of ACC neurons to colorectal distension (CRD) and an increase in the proportion of neurons responding to otherwise subthreshold stimulation, respectively. Long-term, but not acute, oral administration of Menthacarin (60 mg kg-1 day-1) significantly reduced the net excitatory response to CRD in normally responsive control animals and counteracted the development of visceral hyperalgesia and hypersensitivity induced by repeated corticosterone administration and acute mechanical stimulation. The present study shows that, using the CRD method, chronic Menthacarin administration at a clinically relevant dose attenuates the neuronal discharge associated with visceral pain stimuli in the rat ACC, particularly in models of hypersensitivity, suggesting a potential for treating exaggerated visceral pain sensitivity.

Characterization and closed-loop control of infrared thalamocortical stimulation produces spatially constrained single-unit responses.

Deep brain stimulation (DBS) is a powerful tool for the treatment of circuitopathy-related neurological and psychiatric diseases and disorders such as Parkinson's disease and obsessive-compulsive disorder, as well as a critical research tool for perturbing neural circuits and exploring neuroprostheses. Electrically mediated DBS, however, is limited by the spread of stimulus currents into tissue unrelated to disease course and treatment, potentially causing undesirable patient side effects. In this work, we utilize infrared neural stimulation (INS), an optical neuromodulation technique that uses near to midinfrared light to drive graded excitatory and inhibitory responses in nerves and neurons, to facilitate an optical and spatially constrained DBS paradigm. INS has been shown to provide spatially constrained responses in cortical neurons and, unlike other optical techniques, does not require genetic modification of the neural target. We show that INS produces graded, biophysically relevant single-unit responses with robust information transfer in rat thalamocortical circuits. Importantly, we show that cortical spread of activation from thalamic INS produces more spatially constrained response profiles than conventional electrical stimulation. Owing to observed spatial precision of INS, we used deep reinforcement learning (RL) for closed-loop control of thalamocortical circuits, creating real-time representations of stimulus-response dynamics while driving cortical neurons to precise firing patterns. Our data suggest that INS can serve as a targeted and dynamic stimulation paradigm for both open and closed-loop DBS.

Activity-dependent recruitment of inhibition and excitation in the awake mammalian cortex during electrical stimulation

Electrical stimulation is an effective tool for mapping and altering brain connectivity, with applications ranging from treating pharmacology-resistant neurological disorders to providing sensory feedback for neural prostheses. Paramount to the success of these applications is the ability to manipulate electrical currents to precisely control evoked neural activity patterns. However, little is known about stimulation-evoked responses in inhibitory neurons nor how stimulation-evoked activity patterns depend on ongoing neural activity. In this study, we used 2-photon imaging and cell-type specific labeling to measure single-cell responses of excitatory and inhibitory neurons to electrical stimuli in the visual cortex of awake mice. Our data revealed strong interactions between electrical stimulation and pre-stimulus activity of single neurons in awake animals and distinct recruitment and response patterns for excitatory and inhibitory neurons. This work demonstrates the importance of cell-type-specific labeling of neurons in future studies.

Sialic Acid Enhanced the Antistress Capability under Challenging Situations by Increasing Synaptic Transmission

BackgroundIn early life, sialic acid (SA) plays a crucial role in neurodevelopment and neuronal function. However, it remains unclear whether and how SA supplementation in early life promotes behavioral response to stress in adolescence. ObjectivesThis study aimed to examine the effects and mechanisms of SA on the antistress capability under challenging situations. MethodsIn this study, C57BL/6 mice were daily supplemented with 1 μL SA solution/g body weight at the dose of 10 mg/kg/d from postnatal day (PND) 5–45. The antistress behaviors, including open field, elevated plus maze, forced swimming test, and tail suspension test, were performed at PND 46, PND 48, PND 50, and PND 52 to detect the antistress ability of SA, respectively. ResultsOur results showed that SA-treated mice were more active in facing challenging situations. The fiber photometry experiment showed that SA promoted the excitatory neuronal response in the medial prefrontal cortex (mPFC), which was extensively interconnected to stress. Besides, electrophysiological results revealed SA enhanced synaptic transmission rather than neuronal excitability of mPFC excitatory neurons. It was also supported by the increasing spine density of mPFC excitatory neurons. At the molecular amount, the SA elevated the transmitter release-related proteins of mPFC, including Synapsin 1 and vesicular glutamate transporter 1 (VGlut 1). Furthermore, SA supplementation enhanced synaptic transmission mainly by altering the kinetics of synaptic transmission. ConclusionsThe SA supplementation enhanced the response capability to stress under challenging situations, and the enhanced synaptic transmission of mPFC excitatory neurons may be the neurological basis of active response under challenging situations. In general, our findings suggested that SA supplementation in early life can promote stress resistance in adolescence.

Immediate and sustained increases in the activity of vagal preganglionic neurons during exercise and after exercise training.

The brain controls the heart by dynamic recruitment and withdrawal of cardiac parasympathetic (vagal) and sympathetic activity. Autonomic control is essential for the development of cardiovascular responses during exercise, however, the patterns of changes in the activity of the two autonomic limbs, and their functional interactions in orchestrating physiological responses during exercise, are not fully understood. The aim of this study was to characterize changes in vagal parasympathetic drive in response to exercise and exercise training by directly recording the electrical activity of vagal preganglionic neurons in experimental animals (rats). Single unit recordings were made using carbon-fibre microelectrodes from the populations of vagal preganglionic neurons of the nucleus ambiguus (NA) and the dorsal vagal motor nucleus of the brainstem. It was found that (i) vagal preganglionic neurons of the NA and the dorsal vagal motor nucleus are strongly activated during bouts of acute exercise, and (ii) exercise training markedly increases the resting activity of both populations of vagal preganglionic neurons and augments the excitatory responses of NA neurons during exercise. These data show that central vagal drive increases during exercise and provide the first direct neurophysiological evidence that exercise training increases vagal tone. The data argue against the notion of exercise-induced central vagal withdrawal during exercise. We propose that robust increases in the activity of vagal preganglionic neurons during bouts of exercise underlie activity-dependent plasticity, leading to higher resting vagal tone that confers multiple health benefits associated with regular exercise.

Membrane potential dynamics of excitatory and inhibitory neurons in mouse barrel cortex during active whisker sensing.

Neocortical neurons can increasingly be divided into well-defined classes, but their activity patterns during quantified behavior remain to be fully determined. Here, we obtained membrane potential recordings from various classes of excitatory and inhibitory neurons located across different cortical depths in the primary whisker somatosensory barrel cortex of awake head-restrained mice during quiet wakefulness, free whisking and active touch. Excitatory neurons, especially those located superficially, were hyperpolarized with low action potential firing rates relative to inhibitory neurons. Parvalbumin-expressing inhibitory neurons on average fired at the highest rates, responding strongly and rapidly to whisker touch. Vasoactive intestinal peptide-expressing inhibitory neurons were excited during whisking, but responded to active touch only after a delay. Somatostatin-expressing inhibitory neurons had the smallest membrane potential fluctuations and exhibited hyperpolarising responses at whisking onset for superficial, but not deep, neurons. Interestingly, rapid repetitive whisker touch evoked excitatory responses in somatostatin-expressing inhibitory neurons, but not when the intercontact interval was long. Our analyses suggest that distinct genetically-defined classes of neurons at different subpial depths have differential activity patterns depending upon behavioral state providing a basis for constraining future computational models of neocortical function.

Microglia enable cross-modal plasticity by removing inhibitory synapses

Cross-modal plasticity is the repurposing of brain regions associated with deprived sensory inputs to improve the capacity of other sensory modalities. The functional mechanisms of cross-modal plasticity can indicate how the brain recovers from various forms of injury and how different sensory modalities are integrated. Here, we demonstrate that rewiring of the microglia-mediated local circuit synapse is crucial for cross-modal plasticity induced by visual deprivation (monocular deprivation [MD]). MD relieves the usual inhibition of functional connectivity between the somatosensory cortex and secondary lateral visual cortex (V2L). This results in enhanced excitatory responses in V2L neurons during whisker stimulation and a greater capacity for vibrissae sensory discrimination. The enhanced cross-modal response is mediated by selective removal of inhibitory synapse terminals on pyramidal neurons by the microglia in the V2L via matrix metalloproteinase 9 signaling. Our results provide insights into how cortical circuits integrate different inputs to functionally compensate for neuronal damage.

Chlorpromazine, an Inverse Agonist of D1R-Like, Differentially Targets Voltage-Gated Calcium Channel (CaV) Subtypes in mPFC Neurons.

The dopamine receptor type 1 (D1R) and the dopamine receptor type 5 (D5R), which are often grouped as D1R-like due to their sequence and signaling similarities, exhibit high levels of constitutive activity. The molecular basis for this agonist-independent activation has been well characterized through biochemical and mutagenesis in vitro studies. In this regard, it was reported that many antipsychotic drugs act as inverse agonists of D1R-like constitutive activity. On the other hand, D1R is highly expressed in the medial prefrontal cortex (mPFC), a brain area with important functions such as working memory. Here, we studied the impact of D1R-like constitutive activity and chlorpromazine (CPZ), an antipsychotic drug and D1R-like inverse agonist, on various neuronal CaV conductances, and we explored its effect on calcium-dependent neuronal functions in the mouse medial mPFC. Using ex vivo brain slices containing the mPFC and transfected HEK293T cells, we found that CPZ reduces CaV2.2 currents by occluding D1R-like constitutive activity, in agreement with a mechanism previously reported by our lab, whereas CPZ directly inhibits CaV1 currents in a D1R-like activity independent manner. In contrast, CPZ and D1R constitutive activity did not affect CaV2.1, CaV2.3, or CaV3 currents. Finally, we found that CPZ reduces excitatory postsynaptic responses in mPFC neurons. Our results contribute to understanding CPZ molecular targets in neurons and describe a novel physiological consequence of CPZ non-canonical action as a D1R-like inverse agonist in the mouse brain.

Direction selectivity of inhibitory interneurons in mouse barrel cortex differs between interneuron subtypes

GABAergic interneurons represent ∼15% to 20% of all cortical neurons, but their diversity grants them unique roles in cortical circuits. In the barrel cortex, responses of excitatory neurons to stimulation of facial whiskers are direction selective, whereby excitation is maximized over a narrow range of angular deflections. Whether GABAergic interneurons are also direction selective is unclear. Here, we use two-photon-guided whole-cell recordings in the barrel cortex of anesthetized mice and control whisker stimulation to measure direction selectivity in defined interneuron subtypes. Selectivity is ubiquitous in interneurons, but tuning sharpness varies across populations. Vasoactive intestinal polypeptide (VIP) interneurons are as selective as pyramidal neurons, but parvalbumin (PV) interneurons are more broadly tuned. Furthermore, a majority (2/3) of somatostatin (SST) interneurons receive direction-selective inhibition, with the rest receiving direction-selective excitation. Sensory evoked activity in the barrel cortex is thus cell-type specific, suggesting that interneuron subtypes make distinct contributions to cortical representations of stimuli.

Pathology and prevention of brain microvascular and neuronal dysfunction induced by a high-fructose diet in rats.

A high-fructose diet causesmetabolic abnormalities in rats, and the cluster of complications points to microvascular and neuronal disorders of the brain. The aim of this study was to evaluate i) the involvement of microvascular disorders and neuronal plasticity in the deleterious effects of a high-fructose dieton the rat brain and ii) a comparative assessment of the effectiveness of Phytocollection therapy (with antidiabetic, antioxidant, and acetylcholinesterase inhibitory activities) compared to Galantamine as first-line therapy for dementia and Diabeton as first-line therapy for hyperglycemia. The calcium adenosine triphosphate non-injection histoangiological method was used to assess capillary network diameter and density. A high-fructose diet resulted in a significant decrease in the diameter and density of the capillary bed, and pharmacological manipulations had a modulatory effect on microcirculatory adaptive mechanisms. In vivo single-unit extracellular recording was used to investigate short-term plasticity in the medial prefrontal cortex. Differences in the parameters of spike background activity and expression of excitatory and inhibitory responses of cortical neurons have been discovered, allowing for flexibility and neuronal function stabilization in pathology and pharmacological prevention. Integration of the coupling mechanism between microvascular function and neuronal spike activity could delay the progressive decline in cognitive function in rats fed a high fructose diet.

Sleep need-dependent changes in functional connectivity facilitate transmission of homeostatic sleep drive

How the homeostatic drive for sleep accumulates over time and is released remains poorly understood. In Drosophila, we previously identified the R5 ellipsoid body (EB) neurons as putative sleep drive neurons1 and recently described a mechanism by which astrocytes signal to these cells to convey sleep need.2 Here, we examine the mechanisms acting downstream of the R5 neurons to promote sleep. EM connectome data demonstrate that R5 neurons project to EPG neurons.3 Broad thermogenetic activation of EPG neurons promotes sleep, whereas inhibiting these cells reduces homeostatic sleep rebound. Perforated patch-clamp recordings reveal that EPG neurons exhibit elevated spontaneous firing following sleep deprivation, which likely depends on an increase in extrinsic excitatory inputs. Our data suggest that cholinergic R5 neurons participate in the homeostatic regulation of sleep, and epistasis experiments indicate that the R5 neurons act upstream of EPG neurons to promote sleep. Finally, we show that the physical and functional connectivity between the R5 and EPG neurons increases with greater sleep need. Importantly, dual patch-clamp recordings demonstrate that activating R5 neurons induces cholinergic-dependent excitatory postsynaptic responses in EPG neurons. Moreover, sleep loss triggers an increase in the amplitude of these responses, as well as in the proportion of EPG neurons that respond. Together, our data support a model whereby sleep drive strengthens the functional connectivity between R5 and EPG neurons, triggering sleep when a sufficient number of EPG neurons are activated. This process could enable the proper timing of the accumulation and release of sleep drive.

Independent response modulation of visual cortical neurons by attentional and behavioral states

Sensory processing is influenced by cognitive and behavioral states, but how these states interact to modulate responses of individual neurons is unknown. We trained mice in a visual discrimination task wherein they attended to different locations within a hemifield while running or sitting still, enabling us to examine how visual responses are modulated by spatial attention and running behavior. We found that spatial attention improved discrimination performance and strengthened visual responses of excitatory neurons in the primary visual cortex whose receptive fields overlapped with the attended location. Although individual neurons were modulated by both spatial attention and running, the magnitudes of these influences were not correlated. While running-dependent modulation was stable across days, attentional modulation was dynamic, influencing individual neurons to different degrees after repeated changes in attentional states. Thus, despite similar effects on neural responses, spatial attention and running act independently with different dynamics, implying separable mechanisms for their implementation.

An inhibitory brainstem input to dopamine neurons encodes nicotine aversion

Nicotine stimulates the dopamine (DA) system, which is essential for its rewarding effect. Nicotine is also aversive at high doses; yet, our knowledge about nicotine's dose-dependent effects on DA circuits remains limited. Here, we demonstrate that high doses of nicotine, which induce aversion-related behavior in mice, cause biphasic inhibitory and excitatory responses in VTA DA neurons that can be dissociated by distinct projections to lateral and medial nucleus accumben subregions, respectively. Guided by computational modeling, we performed a pharmacological investigation to establish that inhibitory effects of aversive nicotineinvolve desensitization of α4β2 and activation of α7 nicotinic acetylcholine receptors. We identify α7-dependent activation of upstream GABA neurons in the laterodorsal tegmentum (LDT) as a key regulator of heterogeneous DA release following aversive nicotine. Finally, inhibition of LDT GABA terminals in VTA prevents nicotine aversion. Together, our findings provide a mechanistic circuit-level understanding of nicotine's dose-dependent effects on reward and aversion.

The Response Dynamics and Function of Cholinergic and GABAergic Neurons in the Basal Forebrain During Olfactory Learning.

Modulation of neural circuits is essential for flexible sensory perception and decision-making in a changing environment. Cholinergic and GABAergic projections to the olfactory system from the horizontal limb of the diagonal band of Broca (HDB) in the basal forebrain are crucial for odor detection and olfactory learning. Although studies have demonstrated that HDB neurons respond during olfactory learning, how cholinergic and GABAergic neurons differ in their response dynamics and roles in olfactory learning remains unclear. In this study, we examined the response profiles of these two subpopulations of neurons during passive odor exposure and associative olfactory learning. We show that the excitatory responses in both cholinergic and GABAergic neurons tended to habituate during repeated passive odor exposure. However, while these habituated responses were also observed in GABAergic neurons during a go-go task, there was no such habituation in cholinergic neurons. Moreover, the responses to S+ and S− trials diverged in cholinergic neurons once mice learned a go/no-go task. Furthermore, the chemogenetic inactivation of cholinergic neurons in the HDB impaired odor discrimination. Together, these findings suggest that cholinergic neurons in the HDB reflect attention to positive reinforcement and may regulate odor discrimination via top–down inputs to the olfactory system.

Excitatory and Inhibitory Neurons of the Spinal Cord Superficial Dorsal Horn Diverge in Their Somatosensory Responses and Plasticity in Vivo.

The superficial dorsal horn (SDH) of the spinal cord represents the first site of integration between innocuous and noxious somatosensory stimuli. According to gate control theory, diverse populations of excitatory and inhibitory interneurons within the SDH are activated by distinct sensory afferents, and their interplay determines the net nociceptive output projecting to higher pain centers. Although specific SDH cell types are ill defined, numerous classifications schemes find that excitatory and inhibitory neurons fundamentally differ in their morphology, electrophysiology, neuropeptides, and pain-associated plasticity; yet little is known about how these neurons respond over a range of natural innocuous and noxious stimuli. To address this question, we applied an in vivo imaging approach in male mice where the genetically encoded calcium indicator GCaMP6s was expressed either in vGluT2-positive excitatory or vIAAT-positive inhibitory neurons. We found that inhibitory neurons were markedly more sensitive to innocuous touch than excitatory neurons but still responded dynamically over a wide range of noxious mechanical stimuli. Inhibitory neurons were also less sensitive to thermal stimuli than their excitatory counterparts. In a capsaicin model of acute pain sensitization, the responses of excitatory neurons were significantly potentiated to innocuous and noxious mechanical stimuli, whereas inhibitory neural responses were only depressed to noxious stimuli. These in vivo findings show that excitatory and inhibitory SDH neurons diverge considerably in their somatosensory responses and plasticity, as postulated by gate control theory.SIGNIFICANCE STATEMENT Gate control theory posits that opposing spinal excitatory and inhibitory neurons, differently tuned across somatosensory modalities, determine the net nociceptive output to higher pain centers. Little is known about how natural stimuli activate these two neural populations. This study applied an in vivo calcium imaging approach to genetically target these neurons and contrast their responses over a range of innocuous and noxious mechanical and thermal stimuli. Compared with excitatory neurons, we found that inhibitory neurons are more sensitive to innocuous touch and far less sensitive to thermal stimuli. An acute model of pain also revealed that these subtypes undergo divergent mechanosensory plasticity. Our data provide important and novel insights for gate-control inspired models of pain processing.

Effect of Biphasic kHz Field Stimulation on CA1 Pyramidal Neurons in Slices

Electrical stimulation in the kilohertz-frequency range has been successfully used for treatment of various neurological disorders. Nevertheless, the mechanisms underlying this stimulation are poorly understood. To study the effect of kilohertz-frequency electric fields on neuronal membrane biophysics we developed a reliable experimental method to measure responses of single neurons to kilohertz field stimulation in brain slice preparations. In the submerged brain slice pyramidal neurons of the CA1 subfield were recorded in the whole-cell configuration before, during and after stimulation with a biphasic charge balanced electric field at 2kHz, 5kHz or 10 kHz. The slice was placed in a 1 mm gap between two parallel 2 mm long platinum-iridium 0.1 mm diameter wire electrodes. Whole-cell recordings lasted for an hour or longer. Typically, a few 5-10 min long sessions of kHz-field stimulation (kHz-FS) with various frequency/amplitude combinations were applied to assess the type of neuronal response and possible changes of its membrane characteristics. It was found that kHz-field stimulation at all frequencies elicited reproducible excitatory neuronal responses lasting throughout stimulation period, but not after cessation of kHz-FS. During kHz-FS the rheobase usually decreased. In addition, spontaneous firing might be initiated in some silent neurons or became more intense in previously spontaneously active neurons. Response thresholds were in the range of 0.5-2 mA and were higher at higher frequencies. Blockade of glutamatergic synaptic transmission did not alter the magnitude of responses. Inhibitory synaptic input was not changed by kilohertz field stimulation. We conclude that kHz-frequency current applied in brain tissue has an excitatory effect on pyramidal neurons during stimulation. This effect is more prominent and occurs at a lower stimulus intensity at a frequency of 2kHz as compared to 5kHz and 10kHz.

Systemic and intrathecal baclofen produce bladder antinociception in rats

BackgroundBaclofen, a clinically available GABAB receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder nociception.MethodsA series of experiments examined the effects of systemic and spinally administered baclofen on bladder nociception in female anesthetized rats. Models of bladder nociception included those which employed neonatal and adult bladder inflammation to produce bladder hypersensitivity.ResultsCumulative intraperitoneal dosing (1–8 mg/kg IP) and cumulative intrathecal dosing (10–160 ng IT) of baclofen led to dose-dependent inhibition of visceromotor responses (VMRs) to urinary bladder distension (UBD) in all tested models. There were no differences in the magnitude of the analgesic effects of baclofen as a function of inflammation versus no inflammation treatments. Hemodynamic (pressor) responses to UBD were similarly inhibited by IT baclofen as well as UBD-evoked excitatory responses of spinal dorsal horn neurons. The GABAB receptor antagonist, CGP 35,348, antagonized the antinociceptive effects of IT baclofen on VMRs in all tested models but did not affect the magnitude of the VMRs by itself suggesting no tonic GABAB activity was present in this preparation. Tolerance to a seven day continuous IT infusion of baclofen was not observed.ConclusionsThese data provide support for a clinical trial of baclofen as a non-opioid treatment of human bladder pain.

Anesthesia and surgery induce a functional decrease in excitatory synaptic transmission in prefrontal cortex neurons, and intraoperative administration of dexmedetomidine does not elicit the synaptic dysfunction

Postoperative delirium (POD), a syndrome of confusion and inattention, frequently occurs after anesthesia and surgery. The prefrontal cortex (PFC) plays key roles in executive functions and cognitive controls. However, the neuropathogenesis of POD in the PFC remains largely unknown. We investigated whether anesthesia and surgery induced neurofunctional changes in the mouse PFC. After laparotomy was performed under isoflurane anesthesia, PFC neuronal activities were compared at the synaptic level using whole-cell patch-clamp recordings. A battery of behavioral tests measuring natural and learned behaviors, and effects of intraoperative dexmedetomidine were also examined. In the anesthesia/surgery group showing changes in natural and learned behaviors, the frequency of excitatory synaptic responses in PFC pyramidal neurons was decreased after the surgery without any changes in the response kinetics. On the other hand, neuronal intrinsic properties and inhibitory synaptic responses were not changed. In the anesthesia/surgery group administered intraoperative dexmedetomidine, the excitatory synaptic transmission and the behaviors were not altered. These results suggest that anesthesia and surgery induce a functional reduction selectively in the PFC excitatory synaptic transmission, and intraoperative dexmedetomidine inhibits the plastic change in the PFC excitatory synaptic input.