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.

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.

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.

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.

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.

Laterality is Universal Among Fishes but Increasingly Cryptic Among Derived Groups.

Laterality has been studied in several vertebrates, mainly in terms of brain lateralization and behavioral laterality, but morphological asymmetry has not been extensively investigated. Asymmetry in fishes was first described in scale-eating cichlids from Lake Tanganyika, in the form of bilateral dimorphism in which some individuals, when opening their mouths, twist them to the right and others to the left. This asymmetry has a genetic basis, and is correlated with lateralized attack behaviors. This has subsequently been found in fishes from numerous taxa with various feeding habits. The generality of such morphological laterality should thus be investigated in as wide a range of fishes as possible. Using specific indicators of lateral differences in mandibles and head inclination, we find that representative species from all 60 orders of extant gnathostome fishes (both bony and cartilaginous) possess morphological laterality. Furthermore, we identify the same laterality in agnathans (hagfish and lamprey), suggesting that this trait appeared early in fish evolution and has been maintained across fish lineages. However, a comparison of asymmetry among groups of bony fishes reveals, unexpectedly, that phylogenetically more recent-groups possess less asymmetry in body structures. The universality of laterality in fishes indicates a monophyletic origin, and may have been present in the ancestors of vertebrates. Ecological factors, predator-prey interactions in particular, may be key drivers in the evolution and maintenance of dimorphism, and may also be responsible for the cryptic trend of asymmetry in derived groups. Because lungfish and coelacanths share this trait, it is likely that tetrapods also inherited it. We believe that study of this morphological laterality will provide insights into the behavioral and sensory lateralization of vertebrates.

Large-scale somatotopic refinement via functional synapse elimination in the sensory thalamus of developing mice.

Functional synapse elimination and strengthening are crucial developmental processes in the formation of precise neuronal circuits in the somatosensory system, but the underlying alterations in topographical organization are not yet fully understood. To address this issue, we generated transgenic mice in which afferent fibers originating from the whisker-related brain region, called the maxillary principal trigeminal nucleus (PrV2), were selectively visualized with genetically expressed fluorescent protein. We found that functional synapse elimination drove and established large-scale somatotopic refinement even after the thalamic barreloid architecture was formed. Before functional synapse elimination, the whisker sensory thalamus was innervated by afferent fibers not only from the PrV2, but also from the brainstem nuclei representing other body parts. Most notably, only afferent fibers from PrV2 onto a whisker sensory thalamic neuron selectively survived and were strengthened, whereas other afferent fibers were preferentially eliminated via their functional synapse elimination. This large-scale somatotopic refinement was at least partially dependent on somatosensory experience. These novel results uncovered a previously unrecognized role of developmental synapse elimination in the large-scale, instead of the fine-scale, somatotopic refinement even after the initial segregation of the barreloid map.

1 W single-frequency Tm-doped ZBLAN fiber MOPA around 810 nm.

We demonstrate a tunable narrow-linewidth fiber MOPA system around 810 nm for the light source of the Sr optical lattice clock. The coherent cw light source with a wavelength of 813.42 nm was generated by a combination of a narrow linewidth external-cavity laser diode and a Tm-doped ZBLAN fiber amplifier, which was upconversion-pumped by an Yb-doped fiber laser at 1064 nm. The maximum output power of 1.1 W was obtained with the launched power of 17 W, which is the highest power obtained from a Tm-doped fiber amplifier ever reported.

Vascularized versus nonvascularized island median nerve grafts in the facial nerve regeneration and functional recovery of rats for facial nerve reconstruction study.

Histological and physiological basis of the therapeutic efficacy of the vascularized autologous nerve graft in facial nerve regeneration remains poorly understood because of no established rat model. The left median nerve and median artery/vein of Lewis rats were collectively ligated, and harvested as a vascularized island median nerve, which was transplanted to a 7-mm gap in the left buccal branch of facial nerve. Nerve regeneration was investigated. The numbers of myelinated fibers, axon diameter, and myelin thickness were significantly higher in the vascularized nerve graft group than in the nonvascularized nerve graft group. Compound muscle action potential measurement showed that the parameters of vascularized group were similar to those in the intact control group. A vascularized median nerve graft resulted in better facial nerve regeneration outcomes.

Rewiring of afferent fibers in the somatosensory thalamus of mice caused by peripheral sensory nerve transection.

The remodeling of neural circuitry and changes in synaptic efficacy after peripheral sensory nerve injury are considered the basis for functional reorganization in the brain, including changes in receptive fields. However, when or how the remodeling occurs is largely unknown. Here we show the rapid rewiring of afferent fibers in the mature ventral posteromedial thalamic nucleus of mice after transection of the peripheral whisker sensory nerve, using the whole-cell voltage-clamp technique. Transection induced the recruitment of afferent fibers to a thalamic relay neuron within 5-6 d of injury. The rewiring was pathway specific, but not sensory experience dependent or peripheral nerve activity dependent. The newly recruited fibers mediated small EPSCs, and postsynaptic GluA2-containing AMPA receptors were selectively upregulated at the new synapses. This rapid and pathway-specific remodeling of thalamic circuitry may be an initial step in the massive axonal reorganization at supraspinal levels, which occurs months or years after peripheral sensory nerve injury.

Relation between morphological antisymmetry and behavioral laterality in a poeciliid fish.

Many animals show lateral bias in various behaviors. In fish, behavioral laterality has been studied from the perspective of its relation with brain lateralization. On the other hands, in some fishes, head dimorphism (righty or lefty) corresponds to behavioral laterality, such as foraging behavior. To examine the correlation between morphological asymmetry and behavioral laterality associated with brain lateralization, we conducted two behavioral tests (the detour test and fast-start test) using a poeciliid fish, Girardinus metallicus. In both behavioral tests, some individuals tended to move rightward, while others tended to move leftward, in a manner associated with head incline. In the detour-test, righty individuals primarily detoured leftward, whereas lefty individuals primarily detoured rightward. In the fast-start tests, the reverse tendency was seen; righty individuals tended to escape rightward, whereas lefty individuals tended to escape leftward. Such results indicate that brain lateralization may be also associated with morphological asymmetry.

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.

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.

Overexpression of dehydroascorbate reductase, but not monodehydroascorbate reductase, confers tolerance to aluminum stress in transgenic tobacco.

Aluminum (Al) inhibits plant growth partly by causing oxidative damage that is promoted by reactive oxygen species and can be prevented by improving antioxidant capacity. Ascorbic acid (AsA), the most abundant antioxidant in plants, is regenerated by the action of monodehydroascorbate reductase (MDAR) and dehydroascorbate reductase (DHAR). We investigated the role of MDAR and DHAR in AsA regeneration during Al stress using transgenic tobacco (Nicotiana tabacum) plants overexpressing Arabidopsis cytosolic MDAR (MDAR-OX) or DHAR (DHAR-OX). DHAR-OX plants showed better root growth than wild-type (SR-1) plants after exposure to Al for 2 weeks, but MDAR-OX plants did not. There was no difference in Al distribution and accumulation in the root tips among SR-1, DHAR-OX, and MDAR-OX plants after Al treatment for 24 h. However, DHAR-OX plants showed lower hydrogen peroxide content, less lipid peroxidation and lower level of oxidative DNA damage than SR-1 plants, whereas MDAR-OX plants showed the same extent of damage as SR-1 plants. Compared with SR-1 plants, DHAR-OX plants consistently maintained a higher AsA level both with and without Al exposure, while MDAR-OX plants maintained a higher AsA level only without Al exposure. Also, DHAR-OX plants maintained higher APX activity under Al stress. The higher AsA level and APX activity in DHAR-OX plants contributed to their higher antioxidant capacity and higher tolerance to Al stress. These findings show that the overexpression of DHAR, but not of MDAR, confers Al tolerance, and that maintenance of a high AsA level is important to Al tolerance.

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.

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.