Closed-loop brain stimulation augments fear extinction in male rats.

Dysregulated fear reactions can result from maladaptive processing of trauma-related memories. In post-traumatic stress disorder (PTSD) and other psychiatric disorders, dysfunctional extinction learning prevents discretization of trauma-related memory engrams and generalizes fear responses. Although PTSD may be viewed as a memory-based disorder, no approved treatments target pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. Here, we show that closed-loop, SWR triggered neuromodulation of the medial forebrain bundle (MFB) can enhance fear extinction consolidation in male rats. The modified fear memories became resistant to induced recall (i.e., 'renewal' and 'reinstatement') and did not reemerge spontaneously. These effects were mediated by D2 receptor signaling-induced synaptic remodeling in the basolateral amygdala. Our results demonstrate that SWR-triggered closed-loop stimulation of the MFB reward system enhances extinction of fearful memories and reducing fear expression across different contexts and preventing excessive and persistent fear responses. These findings highlight the potential of neuromodulation to augment extinction learning and provide a new avenue to develop treatments for anxiety disorders.

Reinstating olfactory bulb-derived limbic gamma oscillations alleviates depression-like behavioral deficits in rodents.

Although the etiology of major depressive disorder remains poorly understood, reduced gamma oscillations is an emerging biomarker. Olfactory bulbectomy, an established model of depression that reduces limbic gamma oscillations, suffers from non-specific effects of structural damage. Here, we show that transient functional suppression of olfactory bulb neurons or their piriform cortex efferents decreased gamma oscillation power in limbic areas and induced depression-like behaviors in rodents. Enhancing transmission of gamma oscillations from olfactory bulb to limbic structures by closed-loop electrical neuromodulation alleviated these behaviors. By contrast, silencing gamma transmission by anti-phase closed-loop stimulation strengthened depression-like behaviors in naive animals. These induced behaviors were neutralized by ketamine treatment that restored limbic gamma power. Taken together, our results reveal a causal link between limbic gamma oscillations and depression-like behaviors in rodents. Interfering with these endogenous rhythms can affect behaviors in rodent models of depression, suggesting that restoring gamma oscillations may alleviate depressive symptoms.

Developmental Process of a Pronounced Laterality in the Scale-eating Cichlid Fish Perissodus microlepis in Lake Tanganyika.

Lateral preference in behaviors has been widely documented in many vertebrates and invertebrates. Such preferences are strange, puzzling, and on the surface, not adaptive. However, behavioral laterality may increase an individual's fitness as well as foraging accuracy and speed. There is little experimental evidence regarding the developmental process of laterality, and unsolved questions have perplexed researchers for several decades. Related to these issues, here, I review that the scale-eating cichlid Perissodus microlepis found in Lake Tanganyika is a valuable model to address the developmental mechanism of animal laterality. The scale-eating cichlid has pronounced behavioral laterality and uses its asymmetric mouth during feeding events. Recent studies have shown that behavioral laterality in this fish depends on both genetic factors and past experience. The attack-side preference of scale eaters is an acquired trait in an early developmental stage. Juvenile fish empirically learn which side of the prey is more effective for tearing scales and gradually select the dominant side for attacking. However, the superior kinetics of body flexion during the dominant side attack has innate characteristics. Additionally, left-right differences in scale-eater mandibles also develop during ontogeny. Further progress toward understanding the comprehensive mechanisms of laterality should address the following persistent barriers: (1) the effects of phylogenetic constraints and ecological factors on the level of laterality; and (2) the neuronal and molecular mechanisms that produce left-right behavioral differences.

Relationship between body mass index and spinal pathology in community-dwelling older adults.

PURPOSE: To clarify the relationship between body mass index (BMI) and spinal pathologies including spinal sagittal balance, back extensor strength (BES), paraspinal muscle mass, prevalent vertebral fracture, disc degeneration, Modic changes, low back pain, and quality of life (QOL) in community-dwelling older adults. METHODS: This study included 380 participants (age: ≥ 65 years, male/female: 152/228) from the Shiraniwa Study. Multivariate nonlinear regression analysis was used to investigate the relationship between BMI and sagittal vertical axis (SVA), BES, paraspinal muscle mass, visual analog scale (VAS) for low back pain, Oswestry Disability Index (ODI), and EuroQoL-5 Dimension (EQ5D) score after adjusting for sex, age, Hospital Anxiety and Depression Scale score, and Charlson Comorbidity Index. In addition, multiple logistic regression analysis was used to investigate the association between BMI and prevalent vertebral fracture, disc degeneration, and Modic changes. RESULTS: BMI was significantly correlated with SVA, BES, paraspinal muscle mass, VAS, ODI, and EQ5D score. The increase in BMI was associated with the deterioration of all outcomes, which accelerated when the BMI increased from approximately 22-23 kg/m2. Moreover, overweight/obesity was significantly correlated with disc degeneration and Modic changes. CONCLUSION: Increased BMI is significantly associated with spinal pathologies such as SVA, BES, paraspinal muscle mass, VAS, QOL, disc degeneration, and Modic changes. The findings suggest that measures for controlling overweight and obesity among older adults can play an important role in the prevention and treatment of spinal pathologies.

Experience-dependent learning of behavioral laterality in the scale-eating cichlid Perissodus microlepis occurs during the early developmental stage.

Behavioral laterality-typically represented by human handedness-is widely observed among animals. However, how laterality is acquired during development remains largely unknown. Here, we examined the effect of behavioral experience on the acquisition of lateralized predation at different developmental stages of the scale-eating cichlid fish Perissodus microlepis. Naïve juvenile fish without previous scale-eating experience showed motivated attacks on prey goldfish and an innate attack side preference. Following short-term predation experience, naïve juveniles learned a pronounced lateralized attack using their slightly skewed mouth morphology, and improved the velocity and amplitude of body flexion to succeed in foraging scales during dominant-side attack. Naïve young fish, however, did not improve the dynamics of flexion movement, but progressively developed attack side preference and speed to approach the prey through predation experience. Thus, the cichlid learns different aspects of predation behavior at different developmental stages. In contrast, naïve adults lost the inherent laterality, and they neither developed the lateralized motions nor increased their success rate of predation, indicating that they missed appropriate learning opportunities for scale-eating skills. Therefore, we conclude that behavioral laterality of the cichlid fish requires the integration of genetic basis and behavioral experiences during early developmental stages, immediately after they start scale-eating.

The Medial Septum as a Potential Target for Treating Brain Disorders Associated With Oscillopathies.

The medial septum (MS), as part of the basal forebrain, supports many physiological functions, from sensorimotor integration to cognition. With often reciprocal connections with a broad set of peers at all major divisions of the brain, the MS orchestrates oscillatory neuronal activities throughout the brain. These oscillations are critical in generating sensory and emotional salience, locomotion, maintaining mood, supporting innate anxiety, and governing learning and memory. Accumulating evidence points out that the physiological oscillations under septal influence are frequently disrupted or altered in pathological conditions. Therefore, the MS may be a potential target for treating neurological and psychiatric disorders with abnormal oscillations (oscillopathies) to restore healthy patterns or erase undesired ones. Recent studies have revealed that the patterned stimulation of the MS alleviates symptoms of epilepsy. We discuss here that stimulus timing is a critical determinant of treatment efficacy on multiple time scales. On-demand stimulation may dramatically reduce side effects by not interfering with normal physiological functions. A precise pattern-matched stimulation through adaptive timing governed by the ongoing oscillations is essential to effectively terminate pathological oscillations. The time-targeted strategy for the MS stimulation may provide an effective way of treating multiple disorders including Alzheimer's disease, anxiety/fear, schizophrenia, and depression, as well as pain.

Reduced MC4R signaling alters nociceptive thresholds associated with red hair.

Humans and mice with natural red hair have elevated basal pain thresholds and an increased sensitivity to opioid analgesics. We investigated the mechanisms responsible for higher nociceptive thresholds in red-haired mice resulting from a loss of melanocortin 1 receptor (MC1R) function and found that the increased thresholds are melanocyte dependent but melanin independent. MC1R loss of function decreases melanocytic proopiomelanocortin transcription and systemic melanocyte-stimulating hormone (MSH) levels in the plasma of red-haired (Mc1re/e ) mice. Decreased peripheral α-MSH derepresses the central opioid tone mediated by the opioid receptor OPRM1, resulting in increased nociceptive thresholds. We identified MC4R as the MSH-responsive receptor that opposes OPRM1 signaling and the periaqueductal gray area in the brainstem as a central area of opioid/melanocortin antagonism. This work highlights the physiologic role of melanocytic MC1R and circulating melanocortins in the regulation of nociception and provides a mechanistic framework for altered opioid signaling and pain sensitivity in red-haired individuals.

Closed-loop stimulation of the medial septum terminates epileptic seizures.

Temporal lobe epilepsy with distributed hippocampal seizure foci is often intractable and its secondary generalization might lead to sudden death. Early termination through spatially extensive hippocampal intervention is not feasible directly, because of the large size and irregular shape of the hippocampus. In contrast, the medial septum is a promising target to govern hippocampal oscillations through its divergent connections to both hippocampi. Combining this 'proxy intervention' concept and precisely timed stimulation, we report here that closed-loop medial septum electrical stimulation can quickly terminate intrahippocampal seizures and suppress secondary generalization in a rat kindling model. Precise stimulus timing governed by internal seizure rhythms was essential. Cell type-specific stimulation revealed that the precisely timed activation of medial septum GABAergic neurons underlaid the effects. Our concept of time-targeted proxy stimulation for intervening pathological oscillations can be extrapolated to other neurological and psychiatric disorders, and has potential for clinical translation.

Tonic GABAergic Inhibition Is Essential for Nerve Injury-Induced Afferent Remodeling in the Somatosensory Thalamus and Ectopic Sensations.

Peripheral nerve injury induces functional and structural remodeling of neural circuits along the somatosensory pathways, forming the basis for somatotopic reorganization and ectopic sensations, such as referred phantom pain. However, the mechanisms underlying that remodeling remain largely unknown. Whisker sensory nerve injury drives functional remodeling in the somatosensory thalamus: the number of afferent inputs to each thalamic neuron increases from one to many. Here, we report that extrasynaptic γ-aminobutyric acid-type A receptor (GABAAR)-mediated tonic inhibition is necessary for that remodeling. Extrasynaptic GABAAR currents were potentiated rapidly after nerve injury in advance of remodeling. Pharmacological activation of the thalamic extrasynaptic GABAARs in intact mice induced similar remodeling. Notably, conditional deletion of extrasynaptic GABAARs in the thalamus rescued both the injury-induced remodeling and the ectopic mechanical hypersensitivity. Together, our results reveal a molecular basis for injury-induced remodeling of neural circuits and may provide a new pharmacological target for referred phantom sensations after peripheral nerve injury.

Oscillotherapeutics - Time-targeted interventions in epilepsy and beyond.

Oscillatory brain activities support many physiological functions from motor control to cognition. Disruptions of the normal oscillatory brain activities are commonly observed in neurological and psychiatric disorders including epilepsy, Parkinson's disease, Alzheimer's disease, schizophrenia, anxiety/trauma-related disorders, major depressive disorders, and drug addiction. Therefore, these disorders can be considered as common oscillation defects despite having distinct behavioral manifestations and genetic causes. Recent technical advances of neuronal activity recording and analysis have allowed us to study the pathological oscillations of each disorder as a possible biomarker of symptoms. Furthermore, recent advances in brain stimulation technologies enable time- and space-targeted interventions of the pathological oscillations of both neurological disorders and psychiatric disorders as possible targets for regulating their symptoms.

The metabotropic glutamate receptor subtype 1 regulates development and maintenance of lemniscal synaptic connectivity in the somatosensory thalamus.

The metabotropic glutamate receptor subtype 1 (mGluR1) is a major subtype of group I mGluRs, which contributes to the development and plasticity of synapses in the brain. In the sensory thalamus, the thalamocortical neuron receives sensory afferents and massive feedback input from corticothalamic (CT) fibers. Notably, mGluR1 is more concentrated in CT synapses in the sensory thalamus. In the visual thalamus, mGluR1 maintains mature afferent synaptic connectivity. However, it is unknown whether mGluR1 contributes to strengthening of immature synapses or weakening of excess synapses during development and whether mGluR1 at CT synapses heterosynaptically regulates the development or refinement of afferent synapses. Here we investigated the effects of knocking out the gene encoding mGluR1 or pharmacologically blocking cortical activity on the development and maintenance of lemniscal synapses, i.e., the somatosensory afferent synapses, in the ventral posteromedial somatosensory thalamus. mGluR1-knockout (KO) mice exhibited delayed developmental strengthening as well as incomplete elimination and remodeling after maturation of lemniscal synapses. Similar to the phenotypes exhibited by mGluR1-KO mice, pharmacological blockade of somatosensory cortical activity from P12 or P21 for 1 week in wild-type mice perturbed elimination or maintenance of lemniscal synapses, respectively. The same manipulation in mGluR1-KO mice failed to induce additional abnormalities in lemniscal synaptic connectivity. These results suggest that activation of mGluR1, driven by CT input, regulates multiple stages of the development of lemniscal synapses, including strengthening, refinement, and maintenance in the somatosensory thalamus.

Efficacy of continuous local cryotherapy following total hip arthroplasty.

BACKGROUND: Cryotherapy is rarely reported on the usefulness of cryotherapy applied after total hip arthroplasty (THA), and there are no reports about patient satisfaction against the cryotherapy following THA. The aim of this study was whether cryotherapy can be useful for relieving pain, reducing blood loss, and swelling, and improving patient satisfaction after THA. METHODS: Thirty patients who had undergone THA were treated by a controlled cooling device for 72 h following THA (defined as the cryotherapy group). The other 30 patients without cryotherapy were not treated with cryotherapy (defined as the control group). Blood samples (creatine kinase, and C-reactive protein), estimated blood loss, visual analog scale (VAS) of pain score, total doses of diclofenac sodium suppository used for pain relief, thigh swelling, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and adverse outcomes were compared between two groups. RESULTS: Thigh circumference, measured on only day 4 postoperatively, was significantly lower in the cryotherapy than in the control group. Furthermore, patient satisfaction on postoperative days 4 and 7 was significantly higher in the cryotherapy than in the control group. There were no significant differences in other outcomes between groups. CONCLUSIONS: These results support the potential benefit of cryotherapy for the reduction of swelling, and patient satisfaction during postoperative recovery of patients undergoing THA, even in the presence of periarticular injection and tranexamic acid administration for the prevention of postoperative pain and bleeding. Postoperative cryotherapy is a potentially simple, noninvasive, and relatively inexpensive option for post-THA management.

A collagen-coated PGA conduit for interpositional-jump graft with end-to-side neurorrhaphy for treating facial nerve paralysis in rat.

PURPOSE: This study investigated the potential of collagen-coated polyglycolic acid (PGA) tube with interpositional jump graft (IPJG) in rat. MATERIALS AND METHODS: A total of 16 Lewis rats were used in this study. Facial nerve paralysis was created by ligating facial nerve trunk with a ligature clip. The rats were divided into 3 groups. Nerve conduit group (n = 6) were treated by IPJG with collagen-coated PGA tubes between the facial nerve trunks and the hypoglossal nerves. Autograft group (n = 6) were treated by IPJG with the greater auricular nerves. As the control group (n = 4), non-treated-model rats with facial nerve paralysis were used. The number of myelinated fibers, fiber diameter, axon diameter, myelin thickness, and g-ratio, were analyzed histologically at 13 weeks after surgery. Compound muscle action potential (CMAP) and retrograde tracing were measured. RESULT: Although the number of myelinated fibers in autograft group (1957 ± 775) had significantly higher than that of nerve conduit group (90 ± 41, P < .05), the nerve conduit group showed the regeneration of myelinated nerve axons. CMAP amplitude values of the autograft (4706 ± 1154 µV) and the nerve conduit groups (4119 ± 1397 µV) were significantly higher than that of the control group (915 ± 789 µV, P < .05). Retrograde tracing confirmed the double innervation of mimetic muscles by the facial and hypoglossal nucleus in both groups. CONCLUSION: This study showed histologically and physiologically the superior effectiveness of performing IPJG with a collagen-coated PGA conduit in a rat model.

Specialized movement and laterality of fin-biting behaviour in Genyochoromis mento in Lake Malawi.

Several vertebrates, including fish, exhibit behavioural laterality and associated morphological asymmetry. Laterality may increase individual fitness as well as foraging strength, accuracy and speed. However, little is known about which behaviours are affected by laterality or what fish species exhibit obvious laterality. Previous research on the predatory behaviour of the scale-eating Lake Tanganyika cichlid Perissodus microlepis indicates behavioural laterality that reflects asymmetric jaw morphology. The Lake Malawi cichlid Genyochromis mento feeds on the fins of other fish, a behaviour that G. mento developed independently from the Tanganyikan Perissodini scale eaters. We investigated stomach contents and behavioural laterality of predation in aquarium to clarify the functional roles and evolution of laterality in cichlids. We also compared the behavioural laterality and mouth asymmetry of G. mento and P. microlepis The diet of G. mento mostly includes fin fragments, but also scales of several fish species. Most individual G. mento specimens showed significant attack bias favouring the skew mouth direction. However, there was no difference in success rate between attacks from the preferred side and those from the non-preferred side, and no lateralized kinetic elements in predation behaviour. Genyochromismento showed weaker laterality than P. microlepis, partly because of their different feeding habits, the phylogenetic constraints from their shorter evolutionary history and their origin from ancestor Haplochromini omnivorous/herbivorous species. Taken together, this study provides new insights into the functional roles of behavioural laterality: predatory fish aiming for prey that show escape behaviours frequently exhibit lateralized behaviour in predation.

Lateralized expression of left-right axis formation genes is shared by adult brains of lefty and righty scale-eating cichlids.

Variation in the laterality often exists within species and can be maintained by frequency-dependent selection. Although the molecular developmental mechanisms underlying the left-right axis formation have been investigated, the genomic mechanisms underlying variation in laterality remain largely unknown. The scale-eating cichlid Perissodus microlepis in Lake Tanganyika exhibit lateralized predation; lefty individuals with the mouth opening toward the right preferentially attack on the prey's left trunk, while righty individuals with the opposite opening attacks on the right trunk. Here, we performed RNA-sequencing and subsequent confirmation with quantitative-PCR in the telencephalon, optic tectum, and hindbrain of the cichlid and identified five genes (pkd1b, ntn1b, ansn, pde6g, and rbp4l1) that were differentially expressed between the hemispheres regardless of the laterality. Surprisingly, pkd1b and ntn1b are involved in nodal and netrin signalling, respectively, which are important for left-right asymmetry formation during early embryogenesis. This result indicates that nodal- and netrin-related signals may also play important roles in the maintenance of asymmetry in adult brain. By contrast, no genes showed reversal of lateral differences between lefty and righty individuals in any brain regions examined, suggesting that laterality in the scale-eating cichlid does not simply result from inversion of the left-right asymmetry of gene expression.

A method package for electrophysiological evaluation of reconstructed or regenerated facial nerves in rodents.

Compound muscle action potential (CMAP) recording via reconstructed or regenerated motor axons is a critical examination to evaluate newly developed surgical and regeneration techniques. However, there is currently no documentation on technical aspects of CMAP recordings via reconstructed or regenerated facial nerves. We have studied new techniques of plastic surgery and nerve regeneration using a rat facial nerve defect model for years, standardizing an evaluation pipeline using CMAP recordings. Here we describe our CMAP recording procedure in detail as a package including surgical preparation, data acquisition, analysis and troubleshooting. Each resource is available in public repositories and is maintained as a version control system. In addition, we demonstrate that our analytical pipeline can not only be applied to rats, but also mice. Finally, we show that CMAP recordings can be practically combined with other behavioral and anatomical examinations. For example, retrograde motor neuron labeling provides anatomical evidence for physical routes between the facial motor nucleus and its periphery through reconstructed or regenerated facial nerves, in addition to electrophysiological evidence by CMAP recordings from the same animal. •Standardized surgical, recording and analytical procedures for the functional evaluation of reconstructed or regenerated facial nerves of rats, extended to mice.•The functional evaluation can be combined with anatomical evaluations.•The methods described here are maintained in public repositories as version control systems.

Coding of self-motion-induced and self-independent visual motion in the rat dorsomedial striatum.

Evolutionary development of vision has provided us with the capacity to detect moving objects. Concordant shifts of visual features suggest movements of the observer, whereas discordant changes are more likely to be indicating independently moving objects, such as predators or prey. Such distinction helps us to focus attention, adapt our behavior, and adjust our motor patterns to meet behavioral challenges. However, the neural basis of distinguishing self-induced and self-independent visual motions is not clarified in unrestrained animals yet. In this study, we investigated the presence and origin of motion-related visual information in the striatum of rats, a hub of action selection and procedural memory. We found that while almost half of the neurons in the dorsomedial striatum are sensitive to visual motion congruent with locomotion (and that many of them also code for spatial location), only a small subset of them are composed of fast-firing interneurons that could also perceive self-independent visual stimuli. These latter cells receive their visual input at least partially from the secondary visual cortex (V2). This differential visual sensitivity may be an important support in adjusting behavior to salient environmental events. It emphasizes the importance of investigating visual motion perception in unrestrained animals.

Successful Treatment of Adolescents and Young Adults with Philadelphia-Negative Acute Lymphoblastic Leukemia by Novel L-Asparaginase-Intensified Induction Therapy and Cord Blood Transplantation: A Single-Center Decade Report.

A novel induction therapy, including intensive L-asparaginase, was designed in 2007 for patients aged <45 years with Philadelphia-negative acute lymphoblastic leukemia (ALL). We analyzed seven de novo cases and one case of recurrence who received this treatment. The median age was 21 years (range: 16-35 years). Four patients had T-ALL and the others had B-ALL. All the patients achieved complete remission and proceeded to cord blood transplantation. In the median 72-month follow-up, there were no cases of observed mortality or recurrence. Our results indicate scope for further development of both induction therapy and postremission therapy.

Direct effects of transcranial electric stimulation on brain circuits in rats and humans.

Transcranial electric stimulation is a non-invasive tool that can influence brain activity; however, the parameters necessary to affect local circuits in vivo remain to be explored. Here, we report that in rodents and human cadaver brains, ~75% of scalp-applied currents are attenuated by soft tissue and skull. Using intracellular and extracellular recordings in rats, we find that at least 1 mV/mm voltage gradient is necessary to affect neuronal spiking and subthreshold currents. We designed an 'intersectional short pulse' stimulation method to inject sufficiently high current intensities into the brain, while keeping the charge density and sensation on the scalp surface relatively low. We verify the regional specificity of this novel method in rodents; in humans, we demonstrate how it affects the amplitude of simultaneously recorded EEG alpha waves. Our combined results establish that neuronal circuits are instantaneously affected by intensity currents that are higher than those used in conventional protocols.