The retrosplenial cortex has been implicated in processing sensory information and spatial learning, with abnormal neural activity reported in association with psychedelics and in mouse and non-human primate models of autism spectrum disorders (ASDs). The direct role of the retrosplenial cortex in regulating social behaviors remains unclear. In this work, we reveal that neural activity in the retrosplenial agranular cortex (RSA), a subregion of the retrosplenial cortex, is initially activated, then quickly suppressed upon social contact. This up-down phase of RSA neurons is crucial for normal social behaviors. Parvalbumin-positive GABAergic neurons in the hippocampal CA1 region were found to send inhibitory projections to the RSA. Blocking these CA1-RSA inhibitory inputs significantly impaired social behavior. Notably, enhancing the CA1-RSA inhibitory input rescued the social behavior defects in an ASD mouse model. This work suggests a neural mechanism for the salience processing of social behavior and identifies a potential target for ASD intervention using neural modulation approaches.
Animals ; Social Behavior ; CA1 Region, Hippocampal/physiology* ; Mice ; Male ; Autism Spectrum Disorder/physiopathology* ; Mice, Inbred C57BL ; GABAergic Neurons/drug effects* ; Neural Inhibition/drug effects* ; Parvalbumins/metabolism* ; Neural Pathways/physiology* ; Cerebral Cortex/physiology*

It is known that top-down associative inputs terminate on distal apical dendrites in layer 1 while bottom-up sensory inputs terminate on perisomatic dendrites of layer 2/3 pyramidal neurons (L2/3 PyNs) in primary sensory cortex. Since studies on synaptic transmission in layer 1 are sparse, we investigated the basic properties and cholinergic modulation of synaptic transmission in layer 1 and compared them to those in perisomatic dendrites of L2/3 PyNs of rat primary visual cortex. Using extracellular stimulations of layer 1 and layer 4, we evoked excitatory postsynaptic current/potential in synapses in distal apical dendrites (L1-EPSC/L1-EPSP) and those in perisomatic dendrites (L4-EPSC/L4-EPSP), respectively. Kinetics of L1-EPSC was slower than that of L4-EPSC. L1-EPSC showed presynaptic depression while L4-EPSC was facilitating. In contrast, inhibitory postsynaptic currents showed similar paired-pulse ratio between layer 1 and layer 4 stimulations with depression only at 100 Hz. Cholinergic stimulation induced presynaptic depression by activating muscarinic receptors in excitatory and inhibitory synapses to similar extents in both inputs. However, nicotinic stimulation enhanced excitatory synaptic transmission by ~20% in L4-EPSC. Rectification index of AMPA receptors and AMPA/NMDA ratio were similar between synapses in distal apical and perisomatic dendrites. These results provide basic properties and cholinergic modulation of synaptic transmission between distal apical and perisomatic dendrites in L2/3 PyNs of the visual cortex, which might be important for controlling information processing balance depending on attentional state.
Animals ; Automatic Data Processing ; Dendrites ; Depression ; Inhibitory Postsynaptic Potentials ; Kinetics ; Pyramidal Cells ; Rats ; Receptors, AMPA ; Receptors, Muscarinic ; Synapses ; Synaptic Transmission ; Visual Cortex

Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brush-evoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1 (Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury (SNI). Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in naïve but also in ML133-pretreated mice. In contrast, bicuculline, a GABA receptor antagonist, induced only punctate, but not dynamic, allodynia. These results indicated the involvement of glycinergic transmission in the development of dynamic allodynia. We further found that SNI significantly suppressed the frequency, but not the amplitude, of the glycinergic spontaneous inhibitory postsynaptic currents (gly-sIPSCs) in neurons on the lamina II-III border of the spinal dorsal horn, and pretreatment with ML133 prevented the SNI-induced gly-sIPSC reduction. Furthermore, 5 days after SNI, ML133, either by intrathecal administration or acute bath perfusion, and strychnine sensitively reversed the SNI-induced dynamic, but not punctate, allodynia and the gly-sIPSC reduction in lamina IIi neurons, respectively. In conclusion, our results suggest that blockade of Kir2.1 channels in the spinal dorsal horn selectively inhibits dynamic, but not punctate, mechanical allodynia by enhancing glycinergic inhibitory transmission.
Animals ; Bicuculline ; pharmacology ; Disease Models, Animal ; Glycine ; metabolism ; Hyperalgesia ; drug therapy ; etiology ; metabolism ; Imidazoles ; pharmacology ; Inhibitory Postsynaptic Potentials ; drug effects ; physiology ; Male ; Mice, Inbred C57BL ; Neurons ; drug effects ; metabolism ; Neurotransmitter Agents ; pharmacology ; Peripheral Nerve Injuries ; drug therapy ; metabolism ; Phenanthrolines ; pharmacology ; Potassium Channels, Inwardly Rectifying ; antagonists & inhibitors ; metabolism ; Receptors, GABA-A ; metabolism ; Receptors, Glycine ; metabolism ; Strychnine ; pharmacology ; Synaptic Transmission ; drug effects ; physiology ; Tissue Culture Techniques ; Touch

The hypothalamic paraventricular nucleus (PVN) contains two types of neurons projecting to either the rostral ventrolateral medulla (PVN(RVLM)) or the intermediolateral horn (IML) of the spinal cord (PVN(IML)). These two neuron groups are intermingled in the same subdivisions of the PVN and differentially regulate sympathetic outflow. However, electrophysiological evidence supporting such functional differences is largely lacking. Herein, we compared the electrophysiological properties of these neurons by using patch-clamp and retrograde-tracing techniques. Most neurons (>70%) in both groups spontaneously fired in the cell-attached mode. When compared to the PVN(IML) neurons, the PVN(RVLM) neurons had a lower firing rate and a more irregular firing pattern (p < 0.05). The PVN(RVLM) neurons showed smaller resting membrane potential, slower rise and decay times, and greater duration of spontaneous action potentials (p < 0.05). The PVN(RVLM) neurons received greater inhibitory synaptic inputs (frequency, p < 0.05) with a shorter rise time (p < 0.05). Taken together, the results indicate that the two pre-sympathetic neurons differ in their intrinsic and extrinsic electrophysiological properties, which may explain the lower firing activity of the PVN(RVLM) neurons. The greater inhibitory synaptic inputs to the PVN(RVLM) neurons also imply that these neurons have more integrative roles in regulation of sympathetic activity.
Action Potentials ; Animals ; Fires ; Horns ; Inhibitory Postsynaptic Potentials ; Membrane Potentials ; Neurons ; Paraventricular Hypothalamic Nucleus ; Patch-Clamp Techniques ; Spinal Cord ; Spinal Cord Lateral Horn

OBJECTIVE: To unravel the underlying mechanism of minocycline in formalin-induced inflammatory pain, and to investigate the effects of minocycline on synaptic transmission in substantia gela-tinosa (SG) neurons of rat spinal dorsal horn. METHODS: Behavioral and immunohistochemistry experiments: 30 male Sprague-Dawley (SD) rats (3-5 weeks old) were randomly assigned to control (n=8 rats), model (n=8 rats), saline treatment model (n=6 rats) and minocycline treatment model (n=8 rats) groups. The control group was subcutaneously injected with normal saline on the right hindpaws. Acute inflammatory pain model was established by injecting 5% (volume fraction) formalin into the right hindpaws. The rats in the latter two groups received intraperitoneal injection of saline and minocycline 1 h before the formalin injection, respectively. The time of licking and lifting was recorded every 5 min within 1 h after the subcutaneous injection of normal saline or formalin for all the groups, which was continuously recorded for 1 h. One hour after the pain behavioral recording, the spinal cord tissue was removed following transcardial perfusion of 4% paraformaldehyde. The expression of c-Fos protein in spinal dorsal horn was observed by immunohistochemistry. Electrophysiological experiment: In vitro whole-cell patch-clamp recordings were performed in spinal cord parasagittal slices obtained from 26 male SD rats (3-5 weeks old). Two to five neurons were randomly selected from each rat for patch-clamp recording. the effects of minocycline, fluorocitrate and doxycycline on spontaneous excitatory postsynaptic currents (sEPSCs) or spontaneous inhibitory postsynaptic currents (sIPSCs) of SG neurons were investigated. RESULTS: Compared with the control group, both the licking and lifting time and the expression of c-Fos protein in ipsilateral spinal dorsal horn of the model group were significantly increased. Intraperitoneal injection of minocycline largely attenuated the second phase of formalin-induced pain responses (t=2.957, P<0.05). Moreover, c-Fos protein expression was also dramatically reduced in both the superficial lamina (I-II) and deep lamina (III-IV) of spinal dorsal horn (t_I-II=3.912, t_III-IV=2.630, P<0.05). On the other side, bath application of minocycline significantly increased the sIPSCs frequency to 220%±10% (P<0.05) of the control but did not affect the frequency (100%±1%, t=0.112, P=0.951) and amplitude (98%±1%, t=0.273, P=0.167) of sEPSCs and the amplitude (105%±3%, t=0.568, P=0.058) of sIPSCs. However, fluorocitrate and doxycycline had no effect on the frequency [(99%±1%, t=0.366, P=0.099); (102%±1%, t=0.184, P=0.146), respectively] and amplitude [(98%±1%, t=0.208, P=0.253); (99%±1%, t=0.129, P=0.552), respectively] of sIPSCs. CONCLUSION Minocycline can inhibit formalin-induced inflammatory pain and the expression of c-Fos protein in spinal dorsal horn. These effects are probably due to its enhancement in inhibitory synaptic transmission of SG neurons but not its effect on microglial activation or antibiotic action.
Animals ; Anti-Bacterial Agents/pharmacology* ; Formaldehyde ; Inflammation/complications* ; Inhibitory Postsynaptic Potentials ; Male ; Minocycline/pharmacology* ; Pain/prevention & control* ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Spinal Cord

PURPOSE: Naftopidil ((±)-1-[4-(2-methoxyphenyl) piperazinyl]-3-(1-naphthyloxy) propan-2-ol) is prescribed in several Asian countries for lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Previous animal experiments showed that intrathecal injection of naftopidil abolished rhythmic bladder contraction in vivo. Naftopidil facilitated spontaneous inhibitory postsynaptic currents in substantia gelatinosa (SG) neurons in spinal cord slices. These results suggest that naftopidil may suppress the micturition reflex at the spinal cord level. However, the effect of naftopidil on evoked excitatory postsynaptic currents (EPSCs) in SG neurons remains to be elucidated. METHODS: Male Sprague-Dawley rats at 6 to 8 weeks old were used. Whole-cell patch-clamp recordings were made using SG neurons in spinal cord slices isolated from adult rats. Evoked EPSCs were analyzed in Aδ or C fibers. Naftopidil or prazosin, an α1-adrenoceptor blocker, was perfused at 100 μM or 10 μM, respectively. RESULTS: Bath-applied 100 μM naftopidil significantly decreased the peak amplitudes of Aδ and C fiber-evoked EPSCs to 72.0%±7.1% (n=15) and 70.0%±5.5% (n=20), respectively, in a reversible and reproducible manner. Bath application of 10μM prazosin did not inhibit Aδ or C fiber-evoked EPSCs. CONCLUSIONS: The present study suggests that a high concentration of naftopidil reduces the amplitude of evoked EPSCs via a mechanism that apparently does not involve α1-adrenoceptors. Inhibition of evoked EPSCs may also contribute to suppression of the micturition reflex, together with nociceptive stimulation.
Adult ; Animal Experimentation ; Animals ; Asian Continental Ancestry Group ; Baths ; Excitatory Postsynaptic Potentials ; Humans ; In Vitro Techniques* ; Inhibitory Postsynaptic Potentials ; Injections, Spinal ; Lower Urinary Tract Symptoms ; Male ; Nerve Fibers, Unmyelinated ; Neurons* ; Prazosin ; Prostatic Hyperplasia ; Rats ; Rats, Sprague-Dawley ; Reflex ; Spinal Cord ; Substantia Gelatinosa* ; Urinary Bladder ; Urination

Animals choose among sleep, courtship, and feeding behaviors based on the integration of both external sensory cues and internal states; such choices are essential for survival and reproduction. These competing behaviors are closely related and controlled by distinct neural circuits, but whether they are also regulated by shared neural nodes is unclear. Here, we investigated how a set of male-specific P1 neurons controls sleep, courtship, and feeding behaviors in Drosophila males. We found that mild activation of P1 neurons was sufficient to affect sleep, but not courtship or feeding, while stronger activation of P1 neurons labeled by four out of five independent drivers induced courtship, but only the driver that targeted the largest number of P1 neurons affected feeding. These results reveal a common neural node that affects sleep, courtship, and feeding in a threshold-dependent manner, and provide insights into how competing behaviors can be regulated by a shared neural node.
Animals ; Animals, Genetically Modified ; Brain ; cytology ; Courtship ; Drosophila ; Drosophila Proteins ; genetics ; metabolism ; Feeding Behavior ; physiology ; Locomotion ; Male ; Neural Inhibition ; physiology ; Neural Pathways ; physiology ; Neurons ; physiology ; Sex Factors ; Sleep ; physiology

PURPOSE: Modafinil is a wake-promoting agent that has been proposed to improve cognitive performance at the preclinical and clinical levels. Since there is insufficient evidence for modafinil to be regarded as a cognitive enhancer, the aim of this study was to investigate the effects of chronic modafinil administration on behavioral learning in healthy adult rats. METHODS: Y-maze training was used to assess learning performance, and the whole-cell patch clamp technique was used to assess synaptic transmission in pyramidal neurons of the hippocampal CA1 region of rats. RESULTS: Intraperitoneal administration of modafinil at 200 mg/kg or 300 mg/kg significantly improved learning performance. Furthermore, perfusion with 1mM modafinil enhanced the frequency and amplitude of spontaneous postsynaptic currents and spontaneous excitatory postsynaptic currents in CA1 pyramidal neurons in hippocampal slices. However, the frequency and amplitude of spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons were inhibited by treatment with 1mM modafinil. CONCLUSIONS: These results indicate that modafinil improves learning and memory in rats possibly by enhancing glutamatergic excitatory synaptic transmission and inhibiting GABAergic (gamma-aminobutyric acid-ergic) inhibitory synaptic transmission.
Adult ; Animals ; CA1 Region, Hippocampal ; Excitatory Postsynaptic Potentials ; Humans ; Inhibitory Postsynaptic Potentials ; Learning* ; Memory ; Neurons ; Perfusion ; Rats* ; Synaptic Potentials ; Synaptic Transmission*

Isoliquiritigenin (ILTG) is a chalcone compound and shows various pharmacological properties, including antioxidant and anti-inflammatory activities. In recent study, we have reported a novel role of ILTG in sleep through a positive allosteric modulation of gamma-aminobutyric acid type A (GABA(A))-benzodiazepine (BZD) receptors. However, the effect of ILTG in GABA(A)R-mediated synaptic response in brain has not been tested yet. Here we report that ILTG significantly prolonged the decay of spontaneous inhibitory postsynaptic currents (sIPSCs) mediated by GABA(A)R in mouse hippocampal CA1 pyramidal neurons without affecting amplitude and frequency of sIPSCs. This enhancement was fully inhibited by flumazenil (FLU), a specific GABA(A)-BZD receptor antagonist. These results suggest a potential role of ILTG as a modulator of GABAergic synaptic transmission.
Animals ; Brain ; Chalcone* ; Flumazenil ; gamma-Aminobutyric Acid ; Inhibitory Postsynaptic Potentials ; Mice ; Neurons ; Synaptic Transmission

Phasic and tonic gamma-aminobutyric acid(A) (GABA(A)) receptor-mediated inhibition critically regulate neuronal information processing. As these two inhibitory modalities have distinctive features in their receptor composition, subcellular localization of receptors, and the timing of receptor activation, it has been thought that they might exert distinct roles, if not completely separable, in the regulation of neuronal function. Inhibition should be maintained and regulated depending on changes in network activity, since maintenance of excitation-inhibition balance is essential for proper functioning of the nervous system. In the present study, we investigated how phasic and tonic inhibition are maintained and regulated by different signaling cascades. Inhibitory postsynaptic currents were measured as either electrically evoked events or spontaneous events to investigate regulation of phasic inhibition in layer 2/3 pyramidal neurons of the rat visual cortex. Tonic inhibition was assessed as changes in holding currents by the application of the GABA(A) receptor blocker bicuculline. Basal tone of phasic inhibition was maintained by intracellular Ca2+ and Ca2+/calmodulin-dependent protein kinase II (CaMKII). However, maintenance of tonic inhibition relied on protein kinase A activity. Depolarization of membrane potential (5 min of 0 mV holding) potentiated phasic inhibition via Ca2+ and CaMKII but tonic inhibition was not affected. Thus, phasic and tonic inhibition seem to be independently maintained and regulated by different signaling cascades in the same cell. These results suggest that neuromodulatory signals might differentially regulate phasic and tonic inhibition in response to changes in brain states.
Animals ; Automatic Data Processing ; Bicuculline ; Brain ; Calcium-Calmodulin-Dependent Protein Kinase Type 2* ; Cyclic AMP-Dependent Protein Kinases ; Inhibitory Postsynaptic Potentials ; Membrane Potentials ; Nervous System ; Neurons ; Protein Kinases ; Rats* ; Receptors, GABA-A ; Visual Cortex*