Modulation Of Excitability Research Articles

Neuronal oscillations and functional connectivity of paced nostril breathing: A high-density EEG study.

Controlling nostril airflow through hand manipulations is an ancient yoga technique that has been suggested to provide targeted modulation of neuronal excitability and regulation of autonomic function, which is known to be lateralized in the brain. Here, we examined if unilateral and alternate nostril breathing differentially impacts brain network oscillations measured by high-density EEG in healthy control participants with no prior experience in breathing techniques. We found that paced nostril breathing both decreased alpha/mu oscillations over central and parietal areas and increased frontal midline and occipital theta oscillations when comparing to spontaneous breathing. Alternate nostril breathing suppressed alpha/mu oscillation more than left nostril breathing. Unilateral nostril breathing resulted in an ipsilateral increase in alpha connectivity while left nostril breathing increased anterior-posterior midline theta connectivity. In contrast to the EEG results, heart rate, heart rate variability, and cognitive performance assessed with a working memory task did not differ significantly by breathing condition. Our results add to the existent literature on nasal breathing by demonstrating changes in cortical oscillations and connectivity during a task that combined slow breathing with manual nasal pathway modulation.

Determining the effects of transcranial alternating current stimulation on corticomotor excitability and motor performance: A sham-controlled comparison of four frequencies.

Transcranial alternating current stimulation (tACS) modulates brain oscillations and corticomotor plasticity. We examined the effects of four tACS frequencies (20 Hz, 40 Hz, 60 Hz, and 80 Hz) on motor cortex (M1) excitability and motor performance. In a randomised crossover design, 12 adults received 20-minute tACS sessions, with Sham as control. Corticomotor and intracortical excitability, was measured up to 60-minutes post-tACS. Motor performance was evaluated using the Grooved Pegboard Test (GPT) and sensorimotor assessments. Our findings demonstrated frequency-dependent modulation of corticomotor excitability based on MEP amplitude. 20 Hz and 40 Hz tACS reduced MEPs, while 60 Hz and 80 Hz increased MEPs. Inhibition (cortical silent period, SP) was reduced across all tACS frequencies compared to Sham, with 20 Hz and 40 Hz showing consistent reductions, 60 Hz showing effects at post-0 and post-30, and 80 Hz at post- 60. Furthermore, 60 Hz tACS decreased intracortical inhibition at post 0, while intracortical facilitation increased with 20 Hz and 60 Hz at post-0, and 40 Hz at post-60. Motor performance remained unaffected across frequencies. Regression analyses revealed that shorter SP at 60 min post-60 Hz tACS predicted faster reaction times, while greater MEP amplitudes at 60 min following 80 Hz tACS predicted improved hand dexterity. Overall, beta and gamma tACS frequencies modulate M1 excitability, with consistent effects on SP, suggesting potential use in conditions involving SP elongation, such as stroke and Huntington's disease. These findings highlight 60 Hz tACS as a potential tool for motor rehabilitation therapies.

Stimulation Effects Mapping for Optimizing Coil Placement for Transcranial Magnetic Stimulation.

The position and orientation of transcranial magnetic stimulation (TMS) coil, which we collectively refer to as coil placement, significantly affect both the assessment and modulation of cortical excitability. TMS electric field (E-field) simulation can be used to identify optimal coil placement. However, the present E-field simulation required a laborious segmentation and meshing procedure to determine optimal coil placement. We intended to create a framework that would enable us to offer optimal coil placement without requiring the segmentation and meshing procedure. We constructed the stimulation effects map (SEM) framework using the CASIA dataset for optimal coil placement. We used leave-one-subject-out cross-validation to evaluate the consistency of the optimal coil placement and the target regions determined by SEM for the 74 target ROIs in MRI data from the CASIA, HCP15 and HCP100 datasets. Additionally, we contrasted the E-norms determined by optimal coil placements using SEM and auxiliary dipole method (ADM) based on the DP and CASIA II datasets. We provided optimal coil placement in 'head-anatomy-based' (HAC) polar coordinates and MNI coordinates for the target region. The results also demonstrated the consistency of the SEM framework for the 74 target ROIs. The normal E-field determined by SEM was more significant than the value received by ADM. We created the SEM framework using the CASIA database to determine optimal coil placement without segmentation or meshing. We provided optimal coil placement in HAC and MNI coordinates for the target region. The validation of several target ROIs from various datasets demonstrated the consistency of the SEM approach. By streamlining the process of finding optimal coil placement, we intended to make TMS assessment and therapy more convenient.

Changes in Brain Functional Connectivity Underlying the Space-Number Association.

Whether small number magnitudes are inherently represented as lying to the left of larger ones, the space-number association (SNA), is an important issue in mathematical cognition. In this fMRI study, we used a go/no-go implicit association task to investigate the brain activity and functional connectivity underlying the SNA. Arabic digits lower or higher than 5 and left- or right-pointing arrows were alternated as central targets. In a single-code task condition, participants responded to a specific number magnitude and to all arrows or to a specific arrow direction and to all number magnitudes. In a joint-code (JC) condition, responses were provided after congruent, for example, "go when a number is lower than 5 or an arrow points left," or incongruent, for example, "go when a number is lower than 5 or an arrow points right," SNAs. The SNA was only found in the JC condition, where responses were faster with congruent instructions. Analyses of fMRI functional connectivity showed that the SNA was matched with enhanced excitatory inputs from ACC, the left TPJ, and the left inferior frontal gyrus to the left and right intraparietal sulcus (IPS). Incongruent JC trials were associated with enhanced excitatory modulation from ACC to the left and right IPS. These results show that the SNA is associated with enhanced activation of top-down brain control and changes in the functional interaction between the left and right IPS. We conclude that the SNA does not depend on an inherent and bottom-up spatial coding of number magnitudes.

GABAB Receptor Modulation of Membrane Excitability in Human Pluripotent Stem Cell-Derived Sensory Neurons by Baclofen and α-Conotoxin Vc1.1.

GABAB receptor (GABABR) activation is known to alleviate pain by reducing neuronal excitability, primarily through inhibition of high voltage-activated (HVA) calcium (CaV2.2) channels and potentiating G protein-coupled inwardly rectifying potassium (GIRK) channels. Although the analgesic properties of small molecules and peptides have been primarily tested on isolated murine dorsal root ganglion (DRG) neurons, emerging strategies to develop, study, and characterise human pluripotent stem cell (hPSC)-derived sensory neurons present a promising alternative. In this study, hPSCs were efficiently differentiated into peripheral DRG-induced sensory neurons (iSNs) using a combined chemical and transcription factor-driven approach via a neural crest cell intermediate. Molecular characterisation and transcriptomic analysis confirmed the expression of key DRG markers such as BRN3A, ISLET1, and PRPH, in addition to GABABR and ion channels including CaV2.2 and GIRK1 in iSNs. Functional characterisation of GABABR was conducted using whole-cell patch clamp electrophysiology, assessing neuronal excitability under current-clamp conditions in the absence and presence of GABABR agonists baclofen and α-conotoxin Vc1.1. Both baclofen (100 μM) and Vc1.1 (1 μM) significantly reduced membrane excitability by hyperpolarising the resting membrane potential and increasing the rheobase for action potential firing. In voltage-clamp mode, baclofen and Vc1.1 inhibited HVA Ca2+ channel currents, which were attenuated by the selective GABABR antagonist CGP 55845. However, modulation of GIRK channels by GABABRs was not observed in the presence of baclofen or Vc1.1, suggesting that functional GIRK1/2 channels were not coupled to GABABRs in hPSC-derived iSNs. This study is the first to report GABABR modulation of membrane excitability in iSNs by baclofen and Vc1.1, highlighting their potential as a future model for studying analgesic compounds.

Electrical cutaneous stimulation of the foot sole does not enhance rate of torque development during maximal effort isometric plantarflexion in females.

Rate of torque development (RTD) measures how rapidly one can generate torque and is crucial for balance and athletic performance. Fast RTD depends on the rapid recruitment of high threshold motor units (MUs). Cutaneous electrical stimulation has been shown to alter MU excitability, favoring high threshold MUs via reduced recruitment thresholds. A strong coupling exists between foot sole cutaneous mechanoreceptors and motor neurons of lower-limb muscles, yet it remains unknown if cutaneous input can impact RTD via modulation of MU excitability. This study aimed to investigate whether electrical stimulation across the heel could alter plantarflexion RTD. 11 young and healthy females underwent eight sets of five explosive isometric plantarflexion contractions on a dynamometer while sitting with hip, knee and ankle angles of 80°, 110°, and 90°, respectively. All participants achieved>95% voluntary activation of their plantar flexors. Four sets of contractions were performed with heel cutaneous electrical stimulation (1.0ms pulses delivered at 300Hz, at 2×perceptual threshold) and four sets with no stimulation. Instantaneous RTD values were analyzed in 25ms epochs from onset to 250ms. No significant differences were observed between stimulation conditions within each epoch, thus our results suggest that electrical cutaneous stimulation does not alter RTD in this population.

Bio-inspired neuron based on threshold selector and tunnel diode capable of excitability modulation

Bio-inspired neuron based on threshold selector and tunnel diode capable of excitability modulation

A conifer metabolite corrects episodic ataxia type 1 by voltage sensor–mediated ligand activation of Kv1.1

Loss-of-function sequence variants in KCNA1, which encodes the voltage-gated potassium channel Kv1.1, cause Episodic Ataxia Type 1 (EA1) and epilepsy. Due to a paucity of drugs that directly rescue mutant Kv1.1 channel function, current therapeutic strategies for KCNA1-linked disorders involve indirect modulation of neuronal excitability. Native Americans have traditionally used conifer extracts to treat paralysis, weakness, and pain, all of which may involve altered electrical activity and/or Kv1.1 dysfunction specifically. Here, screening conifer extracts, we found that Chamaecyparis pisifera increases wild-type (WT) Kv1.1 activity, as does its prominent metabolite, the abietane diterpenoid pisiferic acid. Uniquely, pisiferic acid also restored function in 12/12 EA1-linked mutant Kv1.1 channels tested in vitro. Crucially, pisiferic acid (1 mg/kg) restored WT function in Kv1.1E283K/+ mice, a model of human EA1. Experimentally validated all-atom molecular dynamics simulations in a neuron-like membrane revealed that the Kv1.1 voltage-sensing domain (VSD) also acts as a ligand-binding domain akin to those of classic ligand-gated channels; binding of pisiferic acid induces a conformational shift in the VSD that ligand-dependently opens the pore. Conifer metabolite pisiferic acid is a promising and versatile therapeutic lead for EA1 and other Kv1.1-linked disorders.

The role of NMDA receptors in fish stress response: Assessments based on physiology of the caudal neurosecretory system and defensive behavior.

Stress strongly influences the physiology and behavior of animals, and leads into a pathological condition and disease. NMDA receptors (NMDARs) play a crucial role in the modulation of neural activity. To understand the role of NMDARs in fish stress response, we used NMDARs agonist aspartate to test the functional role of its input on the Dahlgren cell population in the caudal neurosecretory system (CNSS) of the olive flounder. In addition, the effect of the NMDARs antagonist D-AP5 on the expression of genes of the main secretory products of the CNSS after stress was investigated by using qPCR technology and the effect of the NMDARs antagonist D-AP5 on post-stress behavior was explored by behavioral methods. Ex vivo electrophysiological experiments showed that the NMDARs agonist aspartate enhanced the firing frequency of Dahlgren cells. Additionally, aspartate treatment increased the incidence of cells exhibiting bursting firing pattern, this result is corroborated by the observed upregulation in the expression of ion channels and major hormone genes in the CNSS. Furthermore, the excitatory influence of aspartate was effectively counteracted by NMDARs antagonist D-AP5. Interestingly, NMDARs antagonist D-AP5 treatment also significantly decreased the plasma cortisol levels and the expression of CRH, UI, and UII in CNSS after acute stress. Treatment with D-AP5 effectively attenuated the stress response, as evidenced by alterations in respiratory metabolism, sand-burying behavior, swimming distance, simulated capture, and escape response. In conclusion, modulation of Dahlgren cell excitability in the CNSS by NMDARs contributes to the regulation of the stress response, NMDARs antagonist D-AP5 can effectively suppress stress response in flounder by regulating the stress hormone expression and secretion. CLINICAL TRIAL REGISTRATION: Project code SHOU-DW-2022-032.

Tonic Cold Pain Temporal Summation and Translesional Cold Pressor Test-Induced Pronociception in Spinal Cord Injury: Association with Spontaneous and Below-Level Neuropathic Pain.

Background/Objectives: Although increased nociceptive excitability and deficient endogenous pain modulation are considered key features of pronociception and central sensitization, their contribution to neuropathic pain (NP) characteristics in SCI is unclear. The aim of this study was to characterize tonic cold perception and endogenous pain modulation in individuals with and without SCI-NP, considering the stage and severity of SCI and, secondarily, NP phenotype. Methods: Temporal summation of pain (TSP) and neuropathic features were assessed using the numerical rating scale (NRS) and Douleur Neuropathique 4 screening questionnaire (DN4) during the tonic cold pressor test (CPT, 12 °C 60 s) applied to the dominant hand and foot. CPT-induced pronociception was assessed as change in algometer pressure pain thresholds (PPTs) measured at the V2, C6, and L4 dermatomes. Results: A total of 72 individuals were recruited (age-sex-matched noninjured, n = 24; SCI-NP, n = 24; SCI-noNP, n = 24 [AIS A: n = 12, AIS B-D: n = 12; subacute SCI: n = 12, chronic SCI: n = 12]). TSP in response to the foot CPT was higher in subacute compared to chronic incomplete SCI-NP, while TSP to the hand CPT was significantly higher in chronic compared to the subacute complete SCI-NP group. Evoked pain intensity during the hand CPT correlated with duration of below-level SCI-NP. The hand CPT induced widespread pronociception (lower PPT), which correlated with 7-day non-evoked (spontaneous) pain intensity in individuals with incomplete SCI-NP. Individuals with below-level NP, but not at-level NP, showed higher TSP during the foot CPT and greater hand CPT-induced L4 dermatome pronociception. Conclusions: Collectively, measurements of above and below-level temporal summation of pain and translesional-induced pronociception in the SCI-NP group highlight the role of these mechanisms in widespread central sensitization, spontaneous pain intensity, and spinothalamic tract hyperexcitability, especially in individuals diagnosed with below-level NP.

Trpv1-lineage neuron-expressing Kcnq4 channel modulates itch sensation in mice.

Voltage-gated potassium channel subfamily q member 4 (Kcnq4) is predominantly expressed by hair cells and auditory neurons and regulates the neuronal excitability in the auditory pathway. Although it is further detected in myelinated large-diameter dorsal root ganglia (DRG) neurons in the periphery, the expression and function of Kcnq4 channel in nociceptors remains unknown. Here we showed that Kcnq4 is substantially expressed by unmyelinated small-diameter DRG neurons in both human and mouse. In spite of a dispensable role in acute pain and chronic skin inflammation, Kcnq4 is specifically involved in the regulation of scratching behavior through controlling action potential firing properties, evidenced by the increased neuronal excitability in small-diameter DRG neurons isolated from Kcnq4 deficient mice. Moreover, genetic ablation of Kcnq4 in Trpv1-positive neurons exacerbates both acute and chronic itch behavior in mice. Taken together, our results uncover a functional role of Trpv1-lineage neuron-expressing Kcnq4 channel in the modulation of itch-specific neuronal excitation in the periphery.

Heightened Reticulospinal Excitability after Severe Corticospinal Damage in Chronic Stroke.

After severe corticospinal tract damage poststroke in humans, some recovery of strength and movement proximally is evident. It is possible that alternate motor pathways, such as the reticulospinal tract, may be upregulated to compensate for the loss of corticospinal tract input. We investigated the extent of reticulospinal tract excitability modulation and its inter-dependence on the severity of corticospinal tract damage after stroke in humans. We used a novel startle conditioned transcranial magnetic stimulation paradigm to elicit ipsilateral motor evoked potentials, an index of reticulospinal tract excitability, in 22 chronic stroke participants with mild to severe corticospinal tract damage and 14 neurotypical age-matched controls. We found that ipsilateral motor evoked potential presence was higher in the paretic arm of people with severe corticospinal tract damage compared to their non-paretic arm, people with mild corticospinal tract damage, and age-matched controls. Interestingly, ipsilateral motor evoked potential presence was correlated with motor impairment across the entire stroke cohort, whereby individuals with worse impairment exhibited more frequent ipsilateral motor evoked potentials (ie, higher reticulospinal tract excitability). Following severe corticospinal tract damage, upregulated reticulospinal tract activity may compensate for a loss of corticospinal tract input, providing some proximal recovery of isolated and within-synergy movements, but deficits in performing out of synergy movements and finger fractionation remain. Interventions aimed at modulating the reticulospinal tract could be beneficial or detrimental to ameliorating motor impairment depending on the degree of reliance on this pathway for residual motor output. ANN NEUROL 2024.

Modulation of motor cortex inhibition during manual dexterity tasks: an adaptive threshold hunting study.

Background: The ability to perform intricate movements is crucial for human motor function. The neural mechanisms underlying precision and power grips are incompletely understood. Corticospinal output from M1 is thought to be modulated by GABAA-ergic intracortical networks within M1. Objectives: To investigate the contribution of M1 intracortical inhibition to fine motor control using adaptive threshold hunting with paired-pulse TMS during pinching and grasping tasks. We hypothesised that SICI could be assessed during voluntary activation, and that corticomotor excitability and SICI modulation would be greater during pinch than grasp reflecting corticospinal control. Methods: Seventeen healthy participants performed gradual pinch and grasp tasks. Using an adaptive threshold-hunting method, paired-pulse TMS was applied in the anterior-posterior current direction to assess cortical excitability and SICI in the dominant FDI muscle. SICI and corticomotor excitability were analysed using an LMM. MEP latencies were obtained in LM, PA and AP current directions and compared using paired t-tests. Results: MEP latencies were prolonged with PA and AP coil orientations compared to LM, with AP showing the largest latency. During single-pulse TMS, there was no difference in the TMS intensity required to reach the MEP target during pinching and grasping. Greater inhibition was found during pinching compared to grasping. Conclusion: ATH with paired-pulse TMS permits investigation of intracortical inhibitory networks and their modulation during the performance of dexterous motor tasks revealing a greater modulation of GABAA-ergic inhibition contributing to SICI during pinching compared to grasping.

Methylphenidate reduces spatial attentional bias by modulating fronto-striatal connectivity.

Spatial attention bias reflects tendency to direct attention to specific side in space. This bias reflects asymmetric dopamine (DA) signaling in the striatum. Administration of DA agonists reduces spatial bias, yet the underlying mechanism is not yet clear. To address this, the current study tested whether methylphenidate (MPH; an indirect DA agonist) reduces orienting bias by modulating fronto-striatal connectivity. 54 adults with consistent bias completed the greyscales task which detects subtle biases during fMRI scanning under MPH (20mg) or placebo, in a double-blind design. As hypothesized, MPH reduced bias by increasing orienting towards non-preferred hemispace, regardless of whether the initial bias was left or right. MPH-induced increases were found in activation of the medial superior frontal gyrus (mSFG: F[1;53] = 4.632, cluster-defining threshold of P< 0.05, minimal cluster size = 0, p_FWE = 0.036, η2= 0.08) and its functional connectivity with the caudate (left caudate: F[1;53] = 12.664, p_FWE = 0.001, η2= 0.192; right caudate: F[1;53] = 11.069, p_FWE = 0.002, η2= 0.172), when orienting towards the non-preferred hemispace. MPH also reduced mSFG activation and fronto-striatal connectivity for the preferred hemispace. Results suggest modulation of frontal excitability due to increased caudate-mSFG functional connectivity. This mechanism may underlie the positive effect of dopaminergic agonists on abnormal patterns of directing attention in space.

Subthreshold TMS induced supraspinal modulation of spinal excitability in children and adolescents

Subthreshold TMS induced supraspinal modulation of spinal excitability in children and adolescents

Short-latency afferent inhibition is reduced with cold-water immersion of a limb and remains reduced after removal from the cold stimulus.

The experience of pain that is induced by extremely cold temperatures can exert a modulatory effect on motor cortex circuitry. Although it is known that immersion of a single limb in very cold water can increase corticomotor excitability it is unknown how afferent input to the cortex shapes excitatory and inhibitory processes. Therefore, the purpose of this study was to examine motor-evoked potentials (MEP), short-latency afferent inhibition (SAI) and long-latency afferent inhibition (LAI) in response to immersion of a single hand in cold water. Transcranial magnetic stimulation (TMS) was used to assess MEPs, and peripheral nerve stimulation of the median nerve paired with TMS was used to measure SAI and LAI in motor circuits of the ipsilateral hemisphere. Measurements were obtained from electromyography (EMG) of the first dorsal interosseous (FDI) at baseline, during cold-water immersion, and during recovery from cold-water immersion. The intervention caused unconditioned MEPs to increase during exposure to the cold stimulus (P=0.008) which then returned to baseline levels once the hand was removed from the cold water. MEP responses were decoupled from SAI responses, where SAI was reduced during exposure to the cold stimulus (P=0.005) and remained reduced compared to baseline when the hand was removed from the cold water (P=0.002). The intervention had no effect on LAI. The uncoupling of SAI from MEPs during the recovery period suggests that the mechanisms underlying the modulation of corticospinal excitability by sensory input may be distinct from those affecting intracortical inhibitory circuits. HIGHLIGHTS: What is the central question of this study? Does immersion of a limb in very cold water influence corticospinal excitability and the level of afferent inhibition exerted on motor cortical circuits? What is the main finding and its importance? In additional to perception of temperature, immersion in 6°C water also induced perceptions of pain. Motor evoked potential (MEP) amplitude increased during immersion, and short-latency afferent inhibition (SAI) of the motor cortex was reduced during immersion; however, these responses differed after the limb was removed from the cold stimulus, as MEPs returned to normal levels while SAI remained suppressed.

Repetitive Transcranial Magnetic Stimulation (rTMS) Therapy in Mood Disorders and Generalized Anxiety Disorder (GAD)

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neurostimulation technique increasingly investigated for its therapeutic potential in mood disorders and related brain conditions. This paper using content analysis reviewed literatures and summarized current research on the efficacy and safety of rTMS in treating mood disorders, including major depressive disorder (MDD), bipolar disorder (BD), and Generalized Anxiety Disorders (GAD). Studies suggest that rTMS may offer significant improvements in depressive symptoms and mood regulation, particularly in individuals who have not responded to traditional treatments. Mechanisms of action involve modulation of cortical excitability and neural circuitry implicated in mood regulation. While rTMS demonstrates promise as a well-tolerated intervention with minimal side effects, further research is needed to optimize treatment protocols, identify patient-specific predictors of response, and elucidate long-term outcomes. Understanding the role of rTMS in mood disorder management holds potential for advancing personalized treatment approaches and improving overall patient outcomes. The paper concludes that rTMS is a promising intervention for individuals with major depressive disorder (MDD), and generalized anxiety disorder (GAD). Finally, it was recommended that further studies should be conducted on the efficacy or rTMS on mood disorders generally.

Modulation of Neuronal Excitability and Plasticity by BHLHE41 Conveys Lithium Non-Responsiveness.

Many bipolar disorder (BD) patients are non-responsive to lithium. The mechanisms underlying lithium (non-)responsiveness are largely unknown. By using gene-set enrichment analysis methods, we found that core clock gene-sets are significantly associated with lithium response. Among the top hits was BHLHE41, a modulator of the molecular clock and homeostatic sleep. Since BHLHE41 and its paralog BHLHE40 are functionally redundant, we assessed chronic lithium response in double-knockout mutant mice (DKO). We demonstrated that DKOs are non-responsive to lithium's effect in various behavioral tasks. Cellular assays and patch clamp recordings revealed lowered excitability and reduced lithium-response in prefrontal cortical layer 2/3 DKO neurons and on hippocampal long-term potentiation. Single-cell RNA sequencing identified that lithium deregulated mitochondrial respiration, cation channel and postsynapse associated gene-sets specifically in upper layer excitatory neurons. Our findings show that lithium acts in a highly cell-specific way on neuronal metabolism and excitability and modulates synaptic plasticity depending on BHLHE40/41.

Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior.

Mild traumatic brain injury (mTBI) is a significant health burden due to mTBI-related chronic debilitating cognitive and psychiatric morbidities. Recent evidence from our laboratory suggests a possible dysregulation within reward/motivational circuit function at the level of a subcortical structure, the lateral habenula (LHb), where we demonstrated a causal role for hyperactive LHb in mTBI-induced motivational deficits in self-care grooming behavior in young adult male mice when exposed to mTBI during late adolescence (at ∼8 weeks old). In this study, we extended this observation by further characterizing neurobehavioral effects of this repetitive closed head injury model of mTBI in both young adult male and female mice on LHb excitability, corticotropin releasing factor (CRF) modulation of LHb activity, and behavioral responses of motivation to self-care behavior and approach versus avoidance behavior in the presence of a social- or threat-related stimulus. We show that mTBI increases LHb spontaneous tonic activity in female mice similar to what we previously observed in male mice, as well as promoting LHb neuronal hyperexcitability and hyperpolarization-induced LHb bursting in both male and female mice. Interestingly, mTBI only increases LHb intrinsic excitability in male mice coincident with higher levels of the hyperpolarization-activated cation currents (HCN/Ih) and reduces levels of the M-type potassium currents while potentiating M-currents without altering intrinsic excitability in LHb neurons of female mice. Because persistent dysregulation of brain CRF systems is suggested to contribute to chronic psychiatric morbidities and that LHb neurons are highly responsive to CRF, we tested whether the LHb CRF subsystem becomes engaged following mTBI. We found that in vitro inhibition of CRF receptor type 1 (CRFR1) within the LHb reverses mTBI-induced enhancement of LHb tonic activity and hyperexcitability in both sexes, suggesting that an augmented intra-LHb CRF-CRFR1-mediated signaling contributes to the overall LHb hyperactivity following mTBI. Behaviorally, mTBI diminishes motivation for self-care grooming in female mice as in male mice. mTBI also alters defensive behaviors in the looming shadow task by shifting the innate defensive behaviors toward more passive action locking rather than escape behaviors in response to an aerial threat in both male and female mice, as well as prolonging the latency to escape responses in female mice. While this model of mTBI reduces social preference in male mice, it induces higher social novelty seeking during the novel social encounters in both male and female mice. Overall, our study provides further translational validity for the use of this pre-clinical model of mTBI for investigation of mTBI-related reward circuit dysfunction and mood/motivation-related behavioral deficits in both sexes while uncovering a few sexually dimorphic neurobehavioral effects of this model that may differentially affect young males and females when exposed to this type of mTBI during late adolescence.

Vibrational-Mode-Selective Modulation of Electronic Excitation.

Vibrational-mode-selective modulation of electronic excitation is conducted with a synchronized femtosecond (fs) visible (vis) pulse and a picosecond (ps) infrared (IR) pulse. The mechanism of modulation of vibrational and vibronic relaxation behavior of excited state is investigated with ultrafast vis/IR, IR/IR, and vis-IR/IR transient spectroscopy, optical gating experiments and theoretical calculations. An organic molecule, 4'-(N,N-dimethylamino)-3-methoxyflavone (DMA3MHF) is chosen as the model system. Upon 1608 cm-1 excitation, the skeleton stretching vibration of DMA3MHF is energized, which can significantly change the shape of the absorption, facilitate the radiative decay and promote emission from vibrational excited states. As results, a remarkable enhancement and a slight blueshift in fluorescence are observed. The mode-selective modulation of electronic excitation is not limited in luminescence or photophysics. It is expected to be widely applicable in tuning many photochemical processes.