Inhibitory Reflex Research Articles

Why is prepulse inhibition disrupted in schizophrenia?

Prepulse inhibition (PPI) of acoustic startle reflex is a measure of sensorimotor gating that may reflect the biological processes underlying gaiting impairments in schizophrenia. Although PPI is clinically useful, why PPI is inhibited in schizophrenia is largely unknown.Prepulse inhibition is mediated by M2-like muscarinic acetylcholine receptor on neurons in the caudal pontine reticular nucleus (PnC), activation of this receptor induces Gαi dissociation, and inhibits adenylyl cyclase, resulting in the inhibition of the neurons. On the other hand, the symptoms of schizophrenia are mainly linked to hyperactive dopaminergic activity, mediated by dopamine D2-like receptor. Interestingly, D2-like receptor also uses Gαi. This means that both M2-like acetylcholine receptor and D2-like dopamine receptor use same Gαi-protein, competitively. Thus, chronic over-activation of D2-like receptor observed in schizophrenia may disrupt normal M2-like acetylcholine receptor functions due to their shared coupling to Gαi-proteins, i.e. by reducing the amount of Gαi-protein available for M2-like acetylcholine receptors, resulting in the impairment of PPI.

Effects of parameters of video head impulse testing on visually enhanced vestibulo-ocular reflex and vestibulo-ocular reflex suppression

ObjectiveTo investigate the main effects of some testing and analysis variables on clinically quantified visually enhanced vestibulo-ocular reflex (VVOR) and vestibulo-ocular reflex suppression (VORS) results using video head impulse test. MethodsThis prospective observational clinical study included 19 healthy participants who underwent the VVOR and VORS tests. The effect of demographic variables, head oscillation frequency, rotation direction, visual acuity and analysis time window width and location of the recorded tests on the quantified results of both VVOR and VORS were evaluated. And specifically, for the VORS test the effect of cognitive reinforcement of the participant during testing was evaluated. ResultsA statistically significant difference was observed among the VVOR, non-reinforced VORS, and reinforced VORS tests for mean gain values of 0.91 ± 0.09, 0.6 ± 0.15, and 0.57 ± 0.16, respectively (p < 0.001). The optimized linear mixed-effect model showed a significant influence of frequency on the gain values for the reinforced and non-reinforced VORS tests (p = 0.01 and p = 0.004, respectively). Regarding the gain analysis method, statistically significant differences were found according to the short time interval sample location of the records for the initial location of the VVOR test (p < 0.006) and final location of the reinforced VORS test (p < 0.023). ConclusionSignificant differences were observed in the gain values according to VVOR and VORS testing. Head oscillation frequency is a significant factor that affects the gain values, especially in VORS testing. Moreover, in VORS testing, participant concentration has a significant effect on the test for obtaining suppression gain values. When a short time interval sample is considered for VVOR and VORS testing, intermediate time samples appear the most adequate for both tests. SignificanceThe quantified visually enhanced vestibulo-ocular reflex (VVOR) and vestibulo-ocular reflex suppression (VORS) tests have recently been added to the assortment of available clinical vestibular tests. However, despite the clinical validity of these quantified tests that appear to be of increasing clinical interest, the effects of most of the clinical testing methods and mathematical variables are not well defined.In this research we describe what are the main collecting and analysis variables that could influence to the VVOR and VORS tests. Specially for VORS test, participant concentration on test tasks will have positive effect on the measured vestibulo-ocular reflex (VOR) suppression.

Vestibular impact of Friedreich ataxia in early onset patients

BackgroundFriedreich ataxia (FRDA) is the most frequent form of inherited ataxias. Vestibular and auditory assessments are not commonly part of the check up for these patients despite hearing and balance complaints. Screening of vestibular and auditory function was performed in a large group of young patients with genetically confirmed FRDA.MethodsOur study included 43 patients (7–24 years of age). A complete vestibular assessment was performed including the canals function evaluation at 3 head velocities (bithermal caloric test, earth vertical axis rotation (EVAR) and head impulse test (HIT)) and otolith function evaluation (cervical vestibular evoked myogenic potentials). Information regarding the hearing evaluation of the patients were also retrieved including impedance tympanometry, distortion product otoacoustic emissions (DPOAEs), air and bone conduction audiometry and auditory brainstem response (ABR).ResultsVestibular responses were impaired for canal responses (only at high and middle head velocities) and vestibulospinal otolithic responses. Abnormal neural conduction in the central auditory pathways was frequently observed. Oculomotor abnormalities were frequent, mostly hypermetric saccades and gaze instability. Inhibition of the vestibulo-ocular reflex by fixation was normal.ConclusionsWe show that Friedreich ataxia, even at onset, frequently associate saccadic intrusions, abnormal ABRs and decreased vestibulo-ocular and vestibulospinal responses progressing over time. These sensory impairments combined with ataxia further impair patient’s autonomy. These vestibular, auditory and visual impairments could be used as markers of the severity and progression of the disease. Adding vestibular and auditory testing to Friedreich patient’s evaluation may help physicians improve patient’s management.

Comparison of Adrenaline and Dexmedetomidine in Improving the Cutaneous Analgesia of Mexiletine in Response to Skin Pinpricks in Rats

Background: Adrenaline (Adr) and dexmedetomidine (Dex) are commonly used adjuvants of local anesthetics; however, the difference in the improvement of analgesia of local anesthetics between the 2 adjuvants remains unclear. Objective: The objective of this experimental research was to evaluate the cutaneous analgesic effect of mexiletine (Mex) by coadministration with Dex or Adr. Methods: The effect of a nociceptive block was assessed based on the inhibition of the cutaneous trunci muscle reflex in response to skin pinpricks in rats. The analgesic activity of Mex alone and Mex coadministered with Dex or Adr was evaluated after subcutaneous injections. Subcutaneous injections of drugs or combinations include Mex 0.6, 1.8, and 6.0 μmol; Adr 13.66 nmol; Dex 1.05600 nmol; saline; and Mex 1.8 and 6.0 μmol, respectively, combined with Dex 0.01056, 0.10560, and 1.05600 nmol or Adr 0.55, 2.73, and 13.66 nmol, with each injection dose of 0.6 mL. Results: Subcutaneous injections of Mex elicited dose-related cutaneous analgesia. Compared with Mex (1.8 μmol), adding Dex or Adr to Mex (1.8 μmol) solutions for skin nociceptive block potentiated and prolonged the action. Mex (6.0 μmol) combined with Dex or Adr extended the duration of cutaneous analgesia when compared with Mex (6.0 μmol) alone. A high dose of Adr is more effective with Mex 1.8 μmol than that of Dex, whereas medium and low doses were less effective. Mex 6.0 μmol combined with any dose of Adr is superior to that of Dex. Conclusions: Both Dex and Adr improve the sensory block and enhance the nociceptive block duration of Mex. But in most cases, Adr is superior to Dex. It may be that different mechanisms of action of the 2 adjuvants lead to the differences.

HYR-PB21-LA, a potential extended-release bupivacaine formulation, produces long-lasting local anesthesia in rats and guinea pigs

BackgroundEffective postoperative pain management plays a key role in enhancing recovery of patients after surgery. Bupivacaine hydrochloride is one of the most commonly local anesthetics used for the postoperative pain...

Effects of psychological or physical prenatal stress on attention and locomotion in juvenile rats

Background: Prenatal stress has been shown to affect the cognition of offspring, including memory and learning abilities.Methods: In the current study, the long-term effects of chronic prenatal exposure to the physical or psychological stress on locomotion and attention were evaluated by using open field test (OFT) and prepulse inhibition (PPI) of the acoustic startle reflex (ASR). In addition, the level of corticosterone was measured after the ASR trial.Results: Male and female rodents that underwent prenatal physical and psychological stress had an augmented velocity in OFT, and only male animals showed an increased ASR. Neither male nor female offsprings had an alteration in the level of corticosterone and PPI values regardless of the stress type.Conclusion: Our results revealed that exposure to stress during the development of fetus increases ASR in a sex-dependent manner. This finding might implicate the effect of prenatal stress on attention in male offspring regardless of the stress type.

Elucidation of the purinergic P2X4‐dopamine receptor interaction in regulation of sensorimotor gating and underlying signaling molecules

Purinergic P2X4 receptors (P2X4Rs) are ion channels gated by adenosine‐5′‐triphosphate in the brain. Recent investigations from our laboratory have reported a role for P2X4Rs in regulation of various behaviors including sensorimotor gating, emotional responses to acute stressors, motor behavior and drug reward. Amongst these behaviors, our laboratory was greatly interested in the role of P2X4Rs in regulation of sensorimotor gating considering that disruption of this function has major implications in wide spectrum of psychiatric disorders including schizophrenia, bipolar disorder and autism. Sensorimotor gating is the process by which irrelevant stimuli can be filtered out prior to generation of motor output in response to a sensory stimulus. This process allows an individual to efficiently navigate a stimulus‐laden environment with minimum distraction. Positive modulation of P2X4Rs by ivermectin (IVM) induced deficits in prepulse inhibition (PPI) of acoustic startle reflex, which is a reliable operational measure for sensorimotor gating. Additionally mice deficient in the p2rx4 gene [i.e. (P2X4R KO)] exhibited PPI deficits in comparison to the wildtype (WT) littermates. Interestingly, the PPI deficits in P2X4R KO mice were rescued by DA receptor antagonists indicating an interaction between P2X4Rs and DA receptors in PPI regulation. On the basis of findings from P2X4R KO mouse model, we hypothesized that modulation of DA receptors can regulate the effects of IVM on PPI. This was accomplished by testing the effects of DA receptor antagonists, SCH 23390 (for D1 receptors) (1mg/kg) and raclopride (for D2 receptors) (3 mg/kg) on IVM‐mediated PPI deficits. We also tested the effects of DA receptor agonists, SKF 82958 (for D1 receptors) (0.1mg/kg) and quinpirole (for D2 receptors) (0.1 mg/kg) on IVM‐mediated changes in behavior. To elucidate the mechanisms underlying the behavioral outcomes, we investigated the interaction between IVM and dopaminergic drugs on phosphorylation of signaling molecules linked to PPI including dopamine and cyclic‐AMP regulated phosphoprotein of 32kDa (DARPP‐32), Ca2+/calmodulin kinase II (CaMKII), neuronal nitric oxide synthase (nNOS) and secondary messengers such as guanosine‐3′,5′‐cyclic monophosphate(cGMP) in the ventral striatum . We found that SCH 23390 significantly attenuated the PPI disruptive effects of IVM to a much greater degree than raclopride. On the contrary, quinpirole, but not SKF 82958, potentiated IVM‐mediated PPI disruption. At the molecular level, SCH 23390 and raclopride significantly blocked IVM‐mediated changes in phosphorylation of all the signaling molecules in the ventral striatum. SKF 82958 significantly potentiated IVM’s effects on DARPP‐32 and CaMKIIα phosphorylation in the same brain region. Overall, these findings suggest that pharmacological activation of P2X4Rs can induce dysregulation of signaling cascades downstream of DA receptors which can result in PPI deficits. Finally, these findings represent P2X4Rs as a novel drug target for treatment of disorders with inherent DA dysfunction that can consequentially lead to sensorimotor gating perturbations.Support or Funding InformationNIAAA/NIH AA0224488 (D.L.D)IVM disrupted PPI function that was significantly reversed by SCH 23390 and raclopride (A). Neither of the DA receptor antagonists significantly impacted IVM‐mediated effects on startle magnitude (B). Values represent mean PPI % or startle amplitude ± SEM from 18–22 mice per treatment group. ***P &lt;0.001 versus control group. #P&lt;0.05, ##P&lt;0.01 versus IVM‐treated mice. +++P&lt;0.001 versus SCH 23390‐treated mice and $P&lt;0.05 versus raclopride‐treated mice, Tukey’s multiple comparison test.Figure 1IVM modulated DARPP‐32 phosphorylation via P2X4R potentiation in a D1 receptor‐dependent manner in the ventral striatum. Inter‐dependence between P2X4Rs and D1 receptors in DARPP‐32 phosphorylation may be relevant to DA‐dependent behaviors such as sensorimotor gating (A). The ability of raclopride to block IVM‐mediated changes at behavioral and cellular level indicates a plausible interaction between P2X4Rs and D2 receptors in regulation of DA‐dependent behaviors and signaling pathways (B).Figure 2

L‐Menthol Inhibits Cardiac Sympathoexcitation Caused by Inhaled Irritants in the Spontaneously Hypertensive Rat

Inhalation of irritants (e.g. particulate matter and ozone) triggers various efferent responses through activation of transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (TRPV1) channels expressed on airway vagal afferent nerves. In the airways they cause cough and mucus secretion and in conscious, healthy animals parasympathetic‐mediated reflexes include bradycardia and atrioventricular block. However, inhalation of air pollutants including particulate matter and ozone evokes sympathoexcitation (tachycardia, hypertension) in patients with cardiovascular disease. Interestingly, selective activation of airway vagal afferent nerves in spontaneously hypertensive (SH) rats via inhalation of the TRPA1‐specific agonist allyl isothiocyanate (AITC) evoked sympathetic‐mediated tachycardia and premature ventricular contractions (PVCs) consistent with reflexes evoked by inhaled pollution in patients with cardiovascular disease.Airway reflexes such as cough have been shown to be inhibited by nasal stimulation with L‐menthol via activation of cold‐sensitive trigeminal pathways which regulate brainstem respiratory networks. Here, we investigated the cardiac reflexes evoked by inhalation of L‐menthol (150mg/ml) alone and in combination with AITC (4.7mg/ml) in conscious SH rats. L‐menthol inhalation alone had no effect on heart rate, but, when inhaled during AITC inhalation, L‐menthol selectively inhibited the AITC‐evoked tachyarrhythmia. Inhibition of the AITC‐evoked sympathoexcitatory reflexes was not seen in identical studies performed with inactive D‐menthol (150mg/ml). Therefore, we conclude that pulmonary‐cardiac reflex tachyarrhythmia are reduced by activation of nasal menthol‐sensitive pathways. This data supports the potential for prevention of aberrant irritant‐evoked pulmonary‐cardiac reflexes by nasal menthol treatment.Support or Funding InformationNIH r56

SPARC: Correlation between Patient Characteristics in Gastrointestinal Evaluation using Principal Component Analysis

Introductionanorectal function is complex. Assessment of anorectal physiology and diagnostics for anorectal disorders face problems due to inconsistent results with different technologies and huge inter‐subject variability. This limits development of therapeutic strategies. Devices used to evaluate anorectal function include Fecobionics, EndoFLIP, Anorectal manometry and Ultrasound. The goal of this study was to find correlation in patient characteristics based on data obtained with these measurements.Methodsthe four tests mentioned above were used to evaluate anorectal function in normal subjects and patients with fecal incontinence (FI) or constipation. The data were cleaned by replacing unknown values with the average of measurements, and they were standardized. In total there were 90 measurements and 35 features. The collected data included sex, age (60.0±14.3 years), weight (59.0±9.0 kg), height (1.6±0.1m), FI score (16.8±12.8 with normal values =&lt; 5), constipation score (6.5±4.4 with normal values =&lt; 8), anorectal maximum pressure (46.9±10.1 mmHg), resting pressure (61±25.8 mmHg), expel time (46.3±63.2s), and absence or presentation of rectoanal inhibitory reflex (RAIR), etc. Principal component analysis (PCA) was used to find the contribution of each reduced feature in variance of data and the correlation between features, utilizing singular value decomposition. We used Python and its libraries.Results and Discussionthe variance in data was mostly explained using 25 PCs. The percentage of cumulative variance explained by up to the 1th, 25th and 35th PC was 15%, 98% and 100%, respectively. The PCs provided insights about the relation between features. For example, according to the first PC the maximum pressure, resting pressure, maximum tolerance and age were positively correlated. Also, weight, absence of RAIR and constipation score were positively correlated. However, the latter group of parameters were negatively correlated to the former group. Because the number of patients used in this study were limited results should be interpreted with caution. However, more data are currently being collected, which will be included in our analysis. We plan to extend our analysis to cluster patient data using machine learning.Conclusionsin this study we analyzed data gathered in anorectal evaluation using PCA. Data obtained provided insights about relation between characteristics of the patients. Analysis of data obtained in anorectal evaluation will help to better understand factors involved in anorectal and other gastrointestinal disorders, which could lead to better preventive, diagnostic and therapeutic strategies.Support or Funding InformationNIH SPARC fundingAcknowledgementsNIH SPARC funding.

Stretching our understanding of baroreflex control in humans: evidence of a positive feedback pulmonary baroreflex.

Stretching our understanding of baroreflex control in humans: evidence of a positive feedback pulmonary baroreflex.

A Neuroanatomically Grounded Optimal Control Model of the Compensatory Eye Movement System in Mice.

We present a working model of the compensatory eye movement system in mice. We challenge the model with a data set of eye movements in mice (n =34) recorded in 4 different sinusoidal stimulus conditions with 36 different combinations of frequency (0.1–3.2 Hz) and amplitude (0.5–8°) in each condition. The conditions included vestibular stimulation in the dark (vestibular-ocular reflex, VOR), optokinetic stimulation (optokinetic reflex, OKR), and two combined visual/vestibular conditions (the visual-vestibular ocular reflex, vVOR, and visual suppression of the VOR, sVOR). The model successfully reproduced the eye movements in all conditions, except for minor failures to predict phase when gain was very low. Most importantly, it could explain the interaction of VOR and OKR when the two reflexes are activated simultaneously during vVOR stimulation. In addition to our own data, we also reproduced the behavior of the compensatory eye movement system found in the existing literature. These include its response to sum-of-sines stimuli, its response after lesions of the nucleus prepositus hypoglossi or the flocculus, characteristics of VOR adaptation, and characteristics of drift in the dark. Our model is based on ideas of state prediction and forward modeling that have been widely used in the study of motor control. However, it represents one of the first quantitative efforts to simulate the full range of behaviors of a specific system. The model has two separate processing loops, one for vestibular stimulation and one for visual stimulation. Importantly, state prediction in the visual processing loop depends on a forward model of residual retinal slip after vestibular processing. In addition, we hypothesize that adaptation in the system is primarily adaptation of this model. In other words, VOR adaptation happens primarily in the OKR loop.

Effects of combined 5-HT2A and cannabinoid receptor modulation on a schizophrenia-related prepulse inhibition deficit in mice.

Prepulse inhibition of the startle reflex (PPI) is disrupted in several psychiatric disorders including schizophrenia. Understanding PPI pharmacology may help elucidate the pathophysiology of these disorders and lead to better treatments. Given the advantages of multi-target approaches for complex mental illnesses treatment, we have investigated the interaction between receptors known to modulate PPI (5-HT1A and 5-HT2A) and the neuromodulatory endocannabinoid system. To investigate serotonin and cannabinoid receptor (CBR) co-modulation in a model of PPI disruption relevant to schizophrenia METHODS: Male Swiss mice were pretreated with WIN 55,212-2 (CBR agonist), rimonabant (CB1R inverse agonist), 8-OH-DPAT (5-HT1A/7 agonist), and volinanserin (5-HT2A antagonist) or with a combination of a cannabinoid and a serotonergic drug. PPI disruption was induced by acute administration of MK-801. WIN 55,212-2 and rimonabant did not change PPI nor block MK-801-induced deficits. 8-OH-DPAT increased PPI in control mice and, in a higher dose, inhibited MK-801-induced impairments. Volinanserin also increased PPI in control and MK-801-treated mice, presenting an inverted U-shaped dose-response curve. Co-administration of either cannabinoid ligand with 8-OH-DPAT did not change PPI; however, the combination of volinanserin with rimonabant increased PPI in both control and MK-801-exposed mice. WIN 55,212-2 and rimonabant had similar effects in PPI. Moreover, serotonin and cannabinoid receptors interact to modulate PPI. While co-modulation of CBR and 5-HT1A receptors did not change PPI, a beneficial effect of 5-HT2A and CB1R antagonist combination was detected, possibly mediated through potentiation of 5-HT2A blockade effects by concomitant CB1R blockade.

Exposure to sodium salicylate disrupts VGLUT3 expression in cochlear inner hair cells and contributes to tinnitus.

To examine whether exposure to sodium salicylate disrupts expression of vesicular glutamate transporter 3 (VGLUT3) and whether the alteration in expression corresponds to increased risk for tinnitus. Rats were treated with saline (control) or sodium salicylate (treated) Rats were examined for tinnitus by monitoring gap-pre-pulse inhibition of the acoustic startle reflex (GPIAS). Auditory brainstem response (ABR) was applied to evaluate hearing function after treatment. Rats were sacrificed after injection to obtain the cochlea, cochlear nucleus (CN), and inferior colliculus (IC) for examination of VGLUT3 expression. No significant differences in hearing thresholds between groups were identified (p>0.05). Tinnitus in sodium salicylate-treated rats was confirmed by GPIAS. VGLUT3 encoded by solute carrier family 17 members 8 (SLC17a8) expression was significantly increased in inner hair cells (IHCs) of the cochlea in treated animals, compared with controls (p<0.01). No significant differences in VGLUT3 expression between groups were found for the cochlear nucleus (CN) or IC (p>0.05). Exposure to sodium salicylate may disrupt SLC17a8 expression in IHCs, leading to alterations that correspond to tinnitus in rats. However, the CN and IC are unaffected by exposure to sodium salicylate, suggesting that enhancement of VGLUT3 expression in IHCs may contribute to the pathogenesis of tinnitus.

Spinal Circuits Mediate a Stretch Reflex Between the Upper Limbs in Humans

Inter-limb reflexes play an important role in coordinating behaviors involving different limbs. Previous studies have demonstrated that human elbow muscles express an inter-limb stretch reflex at long-latency (50–100 ms), a timing consistent with a trans-cortical linkage. Here we probe for inter-limb stretch reflexes in the shoulder muscles of human participants. Unexpected torque pulses displaced one or both shoulders while participants adopted a steady posture against background torques. The results demonstrated inter-limb stretch reflexes occurring at short-latency for both shoulder extensors and flexors; the rapid timing (36–50 ms) must involve a spinal linkage for the two arms. Inter-limb stretch reflexes were also observed at long-latency yet they were opposite to the preceding short-latency; when the short-latency stretch reflex was excitatory then the long-latency stretch reflex was inhibitory and vice versa. Comparing the responses to contralateral arm displacement to those during simultaneous displacement of both arms revealed that inhibitory inter-limb stretch reflexes are independent of within-limb stretch reflexes, but that excitatory inter-limb stretch reflexes are suppressed by within-limb stretch reflexes. Our results provide the first demonstration of short-latency inter-limb stretch reflexes in the upper limb of humans and reveal interacting spinal circuits for within-limb and inter-limb stretch reflexes.

Adult conditional knockout of PGC-1α in GABAergic neurons causes exaggerated startle reactivity, impaired short-term habituation and hyperactivity

Interneurons not only contribute to the global balance of activity in cortical networks but also mediate the precise gating of information through specific proteins. Accumulating evidence demonstrates that peroxisome-proliferator-activated receptor-gamma co-activator 1 alpha (PGC-1α) is concentrated in inhibitory interneurons and that it plays an important role in neuropsychiatric diseases. However, the functions of the transcriptional coactivator PGC-1α in sensorimotor gating, short-term habituation and spatial reference memory are still not entirely clear. To investigate the precise involvement of PGC-1α in the progression of psychiatric disorders, we first generated PGC-1α conditional knockout mice through transgenic expression of Cre recombinase under the control of dlx5/6 promoter, Cre-mediated excision events occurred specifically in γ-amino-butyric-acid-(GABA)ergic neurons. Short-term habituation and spatial reference memory in Dlx5/6-Cre::PGC-1αfl/fl mice were evaluated using the novel object recognition test and the Morris water maze test, and sensorimotor gating was measured by prepulse inhibition of the acoustic startle reflex. Protein expression of parvalbumin (PV) in specific brain regions was studied by western blotting, immunofluorescence and immunohistochemistry. Here, we show that mice lacking the PGC-1α gene in GABAergic neurons exhibit deficits in short-term habituation, hyperactivity, reduced prepulse inhibition and exaggerated startle reactivity but normal associative spatial reference memory. In particular, these mice display aberrant salience, whereby more attention is paid to a further copy of the original object (now familiar) (relative to the first presentation of the original object, and relative to the presentation of the novel object). These behavioral dysfunctions were associated with decreased PV expression in the cortex (including somatosensory and motor cortex) as well as in the hippocampus, especially in its CA1 and CA3 regions. Together, these findings draw attention to a hyper-response phenotype of PGC-1α conditional knockout mice and indicate that PGC-1α is a novel regulator of gene expression and function in PV-positive interneurons and a potential therapeutic target for psychiatric disorders associated with PGC-1α dysregulation.

Prepulse Inhibition of the Startle Reflex as a Predictor of Vulnerability to Develop Locomotor Sensitization to Cocaine.

Prepulse inhibition (PPI) of the startle reflex is a measure of sensory-motor synchronization. A deficit in PPI has been observed in psychiatric patients, especially those with schizophrenia and vulnerable subjects, since the neural bases of this disorder are also involved in the regulation of PPI. Recently, we have reported that baseline PPI levels in mice can predict their sensitivity to the conditioned reinforcing effects of cocaine in the conditioned place preference (CPP) paradigm. Mice with a low PPI presented a lower sensitivity to the conditioned rewarding effects of cocaine; however, once they acquired conditioned preference with a higher dose of the drug, a more persistent associative effect of cocaine with respect to environmental cues was evident in these animals when compared with High-PPI mice. Therefore, we proposed that the PPI paradigm can determine subjects with a higher vulnerability to the effects of cocaine. Developing locomotor sensitization after pre-exposure to cocaine is considered an indicator of transitioning from recreational use to a compulsive consumption of the drug. Thus, the aim of the present study was to evaluate whether subjects with a low PPI display a higher locomotor sensitization induced by cocaine. First, male and female OF1 mice were classified as High- or Low-PPI according to their baseline PPI levels. Subsequently, the motor effects induced by an acute dose of cocaine (Experiments 1 and 2) and the development of locomotor sensitization induced by pre-exposure to this drug (Experiments 3 and 4) were recorded using two apparatuses (Ethovision and actimeter). Low-PPI mice presented low sensitivity to the motor effects of an acute dose of cocaine, but a high increase of activity after repeated administration of the drug, thus suggesting a great developed behavioral sensitization. Differences after pretreatment with cocaine vs. saline were more pronounced among Low-PPI subjects than among High-PPI animals. These results endorse our hypothesis that the PPI paradigm can detect subjects who are more likely to display behaviors induced by cocaine and which can increase the risk of developing a cocaine use disorder. Herein, we further discuss whether a PPI deficit can be considered an endophenotype for cocaine use disorder.

The medial agranular cortex mediates attentional enhancement of prepulse inhibition of the startle reflex

The startle reflex, which interferes with on-going cognitive/behavioral activities, is of important protective function for humans and animals. Prepulse inhibition (PPI), as an operational measure of sensorimotor gating, is the suppression of the startle reflex in response to an intense startling stimulus (pulse) when this startling stimulus is shortly preceded by a weaker non-startling stimulus (prepulse). In both humans and laboratory animals, PPI can be enhanced by facilitating selective attention to the prepulse, suggesting that higher-order cognitive/perceptual processes modulate PPI. It has been well known that both the cholinergic system located in the basal forebrain and the deep layers of the superior colliculus in the PPI-mediating circuit are top-down modulated by the medial agranular cortex (AGm), which is a subdivision of the medial prefrontal cortex (PFC) and has wide axonal connections with both cortical regions (including the posterior parietal cortex) and subcortical structures critical for attention/orientation processes. This study investigated whether the AGm is involved in attentional modulation of PPI. The results showed that PPI was enhanced by fear conditioning of the prepulse, and then further enhanced by perceived spatial separation between the conditioned prepulse and a back-ground masking noise based on the auditory precedence effect. Bilateral injection of 2-mM kynurenic acid, a broad spectrum antagonist of glutamate receptors, into the AGm, but not the primary somatosensory cortex, eliminated these two types of attentional enhancement of PPI. Thus, the AGm plays a role in facilitating attention to the prepulse and is involved in the top-down modulation of PPI.

Enhanced somatosensory feedback modulates cutaneous reflexes in arm muscles during self-triggered or prolonged stimulation.

Somatosensory feedback plays important roles in regulating all animal movement. The effects of sensory feedback on spinally mediated neural excitability are widely studied using cutaneous electrical stimulation paradigms. Cutaneous reflex amplitudes are reduced when stimulation is self-triggered instead ofexternally triggered. Altered spinal excitability and motor output are also observed following sustained stimulation with various parameters. Our purpose was to probe for interactions between mode and duration by investigating muscle responses following enhanced cutaneous stimulation. Fifteen neurologically intact participants were recruited. Cutaneous reflexes in the extensor carpi radialis (ECR) were evoked with brief (15ms, 300Hz) or sustained (300ms, 50Hz) stimulation trains. Stimulation was applied to the superficial radial or median nerve at the wrist and triggered by: (1) a computer program (random-triggered); (2) muscle contraction (EMG-triggered); (3) the participant pressing a button themselves (button-triggered). During each condition, isometric contractions were performed with ECR muscle activity maintained at 10, 25, 35, and 50% of maximal voluntary contraction. Stronger inhibitory reflexes were found following brief superficial radial nerve stimulation was EMG-triggered suggesting that modulation of cutaneous reflex excitability is specific to the timing when sensory 'cues' are applied during muscle contraction. No difference was observed following sustained stimulation applied to the superficial radial nerve meaning that brief and sustained stimulation affect the cutaneous pathways differentially. Nerve-specific responses were found between superficial radial and median nerve stimulation, such that greater inhibition was induced by EMG-triggered sustained stimulation to the median nerve. These observations are critical in moving beyond pathway phenomenology toward targeted sensory enhancement and amplified motor output in rehabilitation and training.

Characterization of Auditory and Binaural Spatial Hearing in a Fragile X Syndrome Mouse Model.

The auditory brainstem compares sound-evoked excitation and inhibition from both ears to compute sound source location and determine spatial acuity. Although alterations to the anatomy and physiology of the auditory brainstem have been demonstrated in fragile X syndrome (FXS), it is not known whether these changes cause spatial acuity deficits in FXS. To test the hypothesis that FXS-related alterations to brainstem circuits impair spatial hearing abilities, a reflexive prepulse inhibition (PPI) task, with variations in sound (gap, location, masking) as the prepulse stimulus, was used on Fmr1 knock-out mice and B6 controls. Specifically, Fmr1 mice show decreased PPI compared with wild-type mice during gap detection, changes in sound source location, and spatial release from masking with no alteration to their overall startle thresholds compared with wild-type mice. Last, Fmr1 mice have increased latency to respond in these tasks, suggesting additional impairments in the pathway responsible for reacting to a startling sound. This study further supports data in humans with FXS that show similar deficits in PPI.

Actualización con la clasificación de Londres en la interpretación de la manometría anorrectal de alta resolución

La manometría anorrectal de alta resolución es una prueba diagnóstica utilizada para los trastornos motores y sensitivos anorrectales. Consta de una medición del tono basal y de contracción anal; también valora la maniobra de pujo, reflejo rectoanal inhibitorio (RAIR) y parámetros sensitivos rectales. La interpretación convencional de la manometría anorrectal se enfoca en describir aisladamente la región anatómica disfuncional. Sin embargo, con la clasificación de Londres se busca estandarizar el informe de estos resultados, agrupándolos en trastornos mayores, menores y hallazgos no concluyentes, similar a la clasificación de Chicago para trastornos motores esofágicos.