Neuro-protective effects of increased O-GlcNAcylation by glucosamine in an optic tectum traumatic brain injury model of adult zebrafish.

This study investigated the behavioral and molecular changes in the telencephalon following needle stab-induced injury in the optic tectum of adult zebrafish. At 3 days post-injury (dpi), there was noticeable structural damage to brain tissue and reduced neuronal proliferation in the telencephalon that persisted until 30 dpi. Neurobehavioral deficits observed at 3 dpi included decreased exploratory and social activities and impaired learning and memory (L/M) functions; all of these resolved by 7 dpi. The injury led to a reduction in telencephalic phosphorylated cAMP response element-binding protein and O-GlcNAcylation, both of which were restored by 30 dpi. There was an increase in GFAP expression and nuclear translocation of NF-κB p65 at 3 dpi, which were not restored by 30 dpi. The injury caused decreased O-GlcNAc transferase and increased O-GlcNAcase levels at 3 dpi, normalizing by 30 dpi. Glucosamine (GlcN) treatment at 3 dpi significantly restored O-GlcNAcylation levels and L/M function, also reducing GFAP activation. Glucose treatment recovered L/M function by 7 dpi, but inhibition of the hexosamine biosynthetic pathway by 6-diazo-5-oxo-L-norleucine blocked this recovery. These findings suggest that the O-GlcNAc pathway is a potential therapeutic target for addressing L/M impairment following traumatic brain injury in zebrafish.

Alternating bilateral sensory stimulation alleviates alcohol-induced conditioned place preference via a superior colliculus-VTA circuit.

Alcohol is the most widely used addictive substance, potentially leading to brain damage and genetic abnormalities. Despite its prevalence and associated risks, current treatments have yet to identify effective methods for reducing cravings and preventing relapse. In this study, we find that 4-Hz alternating bilateral sensory stimulation (ABS) effectively reduces ethanol-induced conditioned place preference (CPP) in male mice, while 4-Hz flash light does not exhibit therapeutic effects. Whole-brain c-Fos mapping demonstrates that 4-Hz ABS triggers notable activation in superior colliculus GABAergic neurons (SCGABA). SCGABA forms monosynaptic connections with ventral tegmental area dopaminergic neurons (VTADA), which is implicated in ethanol-induced CPP. Bidirectional chemogenetic manipulation of SC-VTA circuit either replicates or blocks the therapeutic effects of 4-Hz ABS on ethanol-induced CPP. These findings elucidate the role of SC-VTA circuit for alleviating ethanol-related CPP by 4-Hz ABS and point to a non-drug and non-invasive approach that might have potential for treating alcohol use disorder.

Effects of Light Isoflurane Anesthesia on Organization of Direction and Orientation Selectivity in the Superficial Layer of the Mouse Superior Colliculus.

The superior colliculus (SC) is the midbrain center for integrating visual and multimodal sensory information. Neurons in the SC exhibit direction and orientation selectivity. Recent studies reported that neurons with similar preferences formed clusters in the mouse SC (Ahmadlou and Heimel, 2015; Feinberg and Meister, 2015; de Malmazet et al., 2018; Li et al., 2020). However, it remains controversial as to how these clusters are organized within the SC (Inayat et al., 2015; Chen et al., 2021). Here, we found that different brain states (i.e., awake or anesthetized with isoflurane) changed the selectivity of individual SC neurons and organizations of the neuronal population in both male and female mice. Using two-photon Ca2+ imaging, we examined both individual neuronal responses and the spatial patterns of their population responses. Under isoflurane anesthesia, orientation selectivity increased and a larger number of orientation-selective cells were observed when compared with the awake condition, whereas the proportions of direction-selective cells were similar in both conditions. Furthermore, direction- and orientation-selective cells located at closer positions showed more similar preferences, and cluster-like spatial patterns were enhanced. Inhibitory responses of direction-selective neurons were also reduced under isoflurane anesthesia. Thus, the changes in the spatial organization of response patterns were considered to be because of changes in the balance of excitation and inhibition, with excitation dominance, in the local circuits. These results provide new insights into the possibility that the functional organization of feature selectivity in the brain is affected by brain state.SIGNIFICANCE STATEMENT Recent large-scale recording studies are changing our view of visual maps in the superior colliculus (SC), including findings of cluster-like localizations of direction- and orientation-selective neurons. However, results from several laboratories are conflicting regarding the presence of cluster-like organization. Here, we demonstrated that light isoflurane anesthesia affected the direction- and orientation-tuning properties in the mouse superficial SC and that their cluster-like localization pattern was enhanced by the anesthesia. Furthermore, the effect of anesthesia on direction selectivity appeared to be different in the excitatory and inhibitory populations in the SC. Our results suggest that the functional organization of direction and orientation selectivity might be regulated by the excitation-inhibition balance that depends on the brain state.

Electrophysiological and pharmacological characterization of spreading depolarization in the adult zebrafish tectum.

Spreading depolarization (SD) is a slowly propagating wave of neuronal and glial depolarization. A growing number of studies show that SD and SD-like phenomena play a role in neurological disorders such as migraine, stroke, and traumatic brain injury. Despite the clinical importance of SD, its underlying molecular and cellular mechanisms remain elusive, possibly because of insufficient animal model allowing genetic manipulation. Such a model would also allow high-throughput screening for SD-suppressing drug development. To address this, we developed a novel experimental system to study SD using zebrafish. Electrophysiological recordings in the immobilized adult zebrafish revealed that increasing extracellular potassium concentration elicited SD with a large and long-lasting negative shift of direct current (DC) potential in the optic tectum. It also reduced the oscillatory activity in the extracellular field potential and increased the expression of the immediate early gene c-fos. Pharmacological blocking of the N-methyl-d-aspartate (NMDA) glutamate receptor attenuated the propagation of SD, suggesting that glutamatergic neurotransmission mediated tectal SD in zebrafish. Our analyses revealed that the zebrafish tectum and rodent cortex had similar SD kinetics. The current study provides electrophysiological and pharmacological evidence that zebrafish SD and mammal SD are comparable. This zebrafish SD model is suitable for genetic manipulation and cost-effective high-throughput screening. It could pave the way to novel diagnostic and therapeutic methods applicable to SD-associated neurological disorders.NEW & NOTEWORTHY Previous studies have implicated spreading depolarization (SD) in stroke and migraine. Here, we demonstrate SD, for the first time, in the adult zebrafish tectum showing waveform kinetics, c-fos expression, and attenuation by N-methyl-d-aspartate glutamate receptor blocker as observed in the rodent cortex. Since the zebrafish is an animal model amenable to genetic manipulation and chemical screening, this result could pave the way to novel diagnostic and therapeutic methods applicable to SD-associated neurological disorders.

Histone acetyltransferase EP300 regulates the proliferation and differentiation of neural stem cells during adult neurogenesis and regenerative neurogenesis in the zebrafish optic tectum.

Zebrafish have a greater capacity for adult neurogenesis and brain regeneration than mammals. In the adult zebrafish optic tectum (OT), neuroepithelial-like stem cells (NE) contribute to adult neurogenesis, whereas radial glia (RG) contribute to neuronal regeneration after the stab wound injury. The molecular mechanisms regulated by acetylated histone play important roles in these events; however, the functions of histone acetyltransferase (HAT) require further elucidation. The aim of this study was to study the proliferation and differentiation of neural stem cells (NSCs) following treatment with C646, a HAT EP300 inhibitor, to identify the functions of HAT in adult neurogenesis and neuronal regeneration. C646 treatment decreased acetylation of histone 3 lysine 9 in the adult OT. Under physiological conditions, C646 promoted NE proliferation and generation of newborn neurons. EP300 inhibition promoted RG proliferation but suppressed the generation of newborn neurons after the injury. EP300 inhibition downregulated the Notch target genes her4 and her6, which was correlated with NE and RG proliferation in the adult OT. EP300 inhibition regulates the proliferation and differentiation of NSCs by inhibiting histone acetylation and Notch target genes expression, suggesting that the functions of HAT in neurogenesis are opposite to those of histone deacetylase.

Intravitreal Interleukin-2 modifies retinal excitatory circuits and retinocollicular innervation.

Interleukin-2 is a classical immune cytokine whose neural functions have received little attention. Its levels have been found to be increased in some neuropathologies, such as Alzheimer's disease, multiple sclerosis and uveitis. Mechanistically, it has been demonstrated the role of IL-2 in regulating glutamate and acetylcholine transmission, thus being relevant for CNS physiology. In fact, our previous work showed that an acute intravitreal IL-2 injection during retinotectal development promoted contralateral eye axonal plasticity in the superior colliculus, but the involved mechanisms were not explored. So, our present study aimed to investigate the effect of increased intravitreal IL-2 levels on the retinal glutamatergic and cholinergic signalling required for retinotectal normal development. We showed through HRP neuronal tracing that intravitreal IL-2 also induces ipsilateral eye axonal sprouting. Protein level and/or immunolocalization analysis in the retina confirmed IL-2 pathway activation by increased expression of phospho-STAT-3, coupled to transient (24h) reduced levels of Egr1, PSD-95 and nicotinic acetylcholine receptor ß2 subunit, suggesting reduced neural activity and synaptic sites. Also, AChE activity and GluN2B and GluA2 contents were reduced within 96h after IL-2 treatment. Therefore, IL-2-induced retinotectal plasticity might be driven by changes in cholinergic and glutamatergic pathways of the retina.

MPTP toxicity causes vocal, auditory, orientation and movement defects in the echolocation bat.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can damage dopaminergic neurons in the substantia nigra in many mammals with biochemical and cellular changes that are relatively similar to those observed in Parkinson's disease. Our study examined whether MPTP-treated echolocation bats can cause changes in bat echolocation system. By considering ultrasound spectrums, auditory brainstem-evoked potentials and flight trajectories of normal bats, we observed that the vocal, auditory, orientation and movement functions of MPTP-treated bats were significantly impaired, and they exhibited various symptoms resembling those in patients with Parkinson's disease. Our immunohistochemistry and western blot analyses further indicated that expression of vocal-related FOXP2 in the superior colliculus, auditory-related otoferlin in the inferior colliculus, dopamine synthesis-related aromatic l-amino acid decarboxylase in the substantia nigra and dopamine receptor in the striatum was significantly decreased. Furthermore, protein expression related to inflammation, oxidative stress and apoptosis in the substantia nigra was significantly increased in MPTP-treated bats. These results indicate that inflammation, oxidative stress and apoptosis may be instrumental in dopaminergic neurodegeneration in the substantia nigra. The vocal, auditory and orientation and movement dysfunctions of MPTP-treated bats are relatively consistent with symptoms of Parkinson's disease.

Retinal ganglion cell loss and gliosis in the retinofugal projection following intravitreal exposure to amyloid-beta.

Pathological accumulations of amyloid-beta (Aß) peptide are found in retina early in Alzheimer's disease, yet its effects on retinal neuronal structure remain unknown. To investigate this, we injected fibrillized Aß1-42 protein into the eye of adult C57BL/6 J mice and analyzed the retina, optic nerve (ON), and the superior colliculus (SC), the primary retinal target in mice. We found that retinal Aß exposure stimulated microglial activation and retinal ganglion cell (RGC) loss as early as 1-week post-injection. Pathology was not limited to the retina, but propagated into other areas of the central nervous system. Microgliosis spread throughout the retinal projection (retina, ON, and SC), with multiplex protein quantitation demonstrating an increase in endogenously produced Aß in the ON and SC corresponding to the injected retinas. Surprisingly, this pathology spread to the opposite side, with unilateral Aß eye injections driving increased Aß levels, neuroinflammation, and RGC death in the opposite, un-injected retinal projection. As Aß-mediated microglial activation has been shown to propagate Aß pathology, we also investigated the role of the Aß-binding microglial scavenger receptor CD36 in this pathology. Transgenic mice lacking the CD36 receptor were resistant to Aß-induced inflammation and RGC death up to 2 weeks following exposure. These results indicate that Aß pathology drives regional neuropathology in the retina and does not remain isolated to the affected eye, but spreads throughout the nervous system. Further, CD36 may serve as a promising target to prevent Aß-mediated inflammatory damage.

Histone deacetylase inhibition promotes regenerative neurogenesis after stab wound injury in the adult zebrafish optic tectum.

The central nervous system (CNS) of adult zebrafish is capable of recovering from injury, unlike the CNS of mammals such as humans or rodents. Previously, we established a stab wound injury model of the optic tectum (OT) in the adult zebrafish and showed that the radial glial cells (RG) proliferation and neuronal differentiation contributes to OT regeneration. In the present study, we analyzed the function of histone deacetylases (HDACs) as potential regulators of OT regeneration. The expression of both hdac1 and hdac3 was found to be significantly decreased in the injured OT. In order to analyze the roles of HDACs in RG proliferation and differentiation after injury, we performed pharmacological experiments using the HDAC inhibitor trichostatin A. We found that HDAC inhibition after stab wound injury suppressed RG proliferation but promoted neuronal differentiation. Moreover, HDAC inhibition suppressed the injury-induced decline in expression of Notch signaling target genes, her4.1 and her6 after OT injury. These results suggest that HDACs regulate regenerative neurogenesis through changes in Notch target gene expression by histone deacetylation. HDACs and histone acetylation are promising molecular targets for neuronal regeneration and further studies about the molecular mechanisms behind the regulation of regeneration by histone acetylation are necessary.

Visuomotor deficiency in panx1a knockout zebrafish is linked to dopaminergic signaling.

Pannexin 1 (Panx1) forms ATP-permeable membrane channels that play roles in the nervous system. The analysis of roles in both standard and pathological conditions benefits from a model organism with rapid development and early onset of behaviors. Such a model was developed by ablating the zebrafish panx1a gene using TALEN technology. Here, RNA-seq analysis of 6 days post fertilization larvae were confirmed by Real-Time PCR and paired with testing visual-motor behavior and in vivo electrophysiology. Results demonstrated that loss of panx1a specifically affected the expression of gene classes representing the development of the visual system and visual processing. Abnormal swimming behavior in the dark and the expression regulation of pre-and postsynaptic biomarkers suggested changes in dopaminergic signaling. Indeed, altered visuomotor behavior in the absence of functional Panx1a was evoked through D1/D2-like receptor agonist treatment and rescued with the D2-like receptor antagonist Haloperidol. Local field potentials recorded from superficial areas of the optic tectum receiving input from the retina confirmed abnormal responses to visual stimuli, which resembled treatments with a dopamine receptor agonist or pharmacological blocking of Panx1a. We conclude that Panx1a functions are relevant at a time point when neuronal networks supporting visual-motor functions undergo modifications preparing for complex behaviors of freely swimming fish.

Fictive Scratching Patterns in Brain Cortex-Ablated, Midcollicular Decerebrate, and Spinal Cats.

Background: The spinal cord's central pattern generators (CPGs) have been explained by the symmetrical half-center hypothesis, the bursts generator, computational models, and more recently by connectome circuits. Asymmetrical models, at odds with the half-center paradigm, are composed of extensor and flexor CPG modules. Other models include not only flexor and extensor motoneurons but also motoneuron pools controlling biarticular muscles. It is unknown whether a preferred model can explain some particularities that fictive scratching (FS) in the cat presents. The first aim of this study was to investigate FS patterns considering the aiming and the rhythmic periods, and second, to examine the effects of serotonin (5HT) on and segmental inputs to FS. Methods: The experiments were carried out first in brain cortex-ablated cats (BCAC), then spinalized (SC), and for the midcollicular (MCC) preparation. Subjects were immobilized and the peripheral nerves were used to elicit the Monosynaptic reflex (MR), to modify the scratching patterns and for electroneurogram recordings. Results: In BCAC, FS was produced by pinna stimulation and, in some cases, by serotonin. The scratching aiming phase (AP) initiates with the activation of either flexor or extensor motoneurons. Serotonin application during the AP produced simultaneous extensor and flexor bursts. Furthermore, WAY 100635 (5HT1A antagonist) produced a brief burst in the tibialis anterior (TA) nerve, followed by a reduction in its electroneurogram (ENG), while the soleus ENG remained silent. In SC, rhythmic phase (RP) activity was recorded in the soleus motoneurons. Serotonin or WAY produced FS bouts. The electrical stimulation of Ia afferent fibers produced heteronymous MRes waxing and waning during the scratch cycle. In MCC, FS began with flexor activity. Electrical stimulation of either deep peroneus (DP) or superficial peroneus (SP) nerves increased the duration of the TA electroneurogram. Medial gastrocnemius (MG) stretching or MG nerve electrical stimulation produced a reduction in the TA electroneurogram and an initial MG extensor burst. MRes waxed and waned during the scratch cycle. Conclusion: Descending pathways and segmental afferent fibers, as well as 5-HT and WAY, can change the FS pattern. To our understanding, the half-center hypothesis is the most suitable for explaining the AP in MCC.

d-Glucuronolactone attenuates para-xylene-induced defects in neuronal development and plasticity in Xenopus tectum in vivo.

Xylene and its derivatives are known to be neurotoxic to the central nervous system of animals. Our previous work has shown that para-xylene (PX) can cause an increase in apoptotic cells and abnormal avoidance behavior in Xenopus laevis. However, the mechanism underlying the impact of PX on neuronal structural and functional plasticity is less clear. Here, we examined the effects of PX on neuronal development and plasticity in the developing optic tectum. We found that HuC/D-positive neurons were more vulnerable than SOX2-positive progenitor cells or BLBP-positive radial glial cells after exposure to PX at 1 mM for 48 h. The further measurement of postsynaptic receptors and synaptic vesicle proteins showed that the expression levels of GluA1 and GluA2, but not Rab3a and SNAP25, were significantly decreased in the tectal brain. In vivo time-lapse images and electrophysiological recordings showed that PX exposure resulted in significant deficits in neuronal structure, particularly in the total dendritic branch length (TDBL), and visual stimulation-induced excitatory compound synaptic currents (eCSCs) without altering neurotransmitter release probability. Strikingly, coexposure to d-glucuronolactone (GA) and PX rescued the structural and functional deficits caused by PX exposure alone. Furthermore, we found that visual experience-induced structural, functional and behavioral plasticity was blocked by PX exposure, which was also rescued by the simultaneous administration of GA and PX . Thus, our findings indicate that PX is neurotoxic to brain development and plasticity and that GA may be considered a promising candidate to treat PX-induced defects in neural circuits.

Enhancing the efficacy of 5-HT uptake inhibitors in the treatment of attention deficit hyperactivity disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common childhood behavioural disorders, the frontline treatments for which are drugs with abuse potential. As a consequence, there is an urgent need to develop non addictive drug treatments with equivalent efficacy. Preclinical evidence suggests that selective serotonin uptake inhibitors (SSRIs) are likely to be effective in ADHD, however clinical reports suggest that SSRIs are of limited therapeutic value for the treatment of ADHD. We propose that this disconnect can be explained by the pattern of drug administration in existing clinical trials (administration for short periods of time, or intermittently) leading to inadequate control of the autoregulatory processes which control 5-HT release, most notably at the level of inhibitory 5-HT1A somatodendritic autoreceptors. These autoreceptors reduce the firing rate of 5-HT neurons (limiting release) unless they are desensitised by a long term, frequent pattern of drug administration. As such, we argue that the participants in earlier trials were not administered SSRIs in a manner which realises any potential benefits of targeting 5-HT in the pharmacotherapy of ADHD. In light of this, we hypothesise that there may be under-researched potential to exploit 5-HT transmission therapeutically in ADHD, either through changing the administration regime, or by pharmacological means. Recent pharmacological research has successfully potentiated the effects of SSRIs in acute animal preparations by antagonising inhibitory 5-HT1A autoreceptors prior to the administration of the SSRI fluoxetine. We suggest that combination therapies linking SSRIs and 5-HT1A antagonists are a potential way forward in the development of efficacious non-addictive pharmacotherapies for ADHD.

Sodium nitroprusside prevents the detrimental effects of glucose on the neurovascular unit and behaviour in zebrafish.

Diabetes is associated with dysfunction of the neurovascular unit, although the mechanisms of this are incompletely understood and currently no treatment exists to prevent these negative effects. We previously found that the nitric oxide (NO) donor sodium nitroprusside (SNP) prevents the detrimental effect of glucose on neurovascular coupling in zebrafish. We therefore sought to establish the wider effects of glucose exposure on both the neurovascular unit and on behaviour in zebrafish, and the ability of SNP to prevent these. We incubated 4-days post-fertilisation (dpf) zebrafish embryos in 20 mM glucose or mannitol for 5 days until 9 dpf, with or without 0.1 mM SNP co-treatment for 24 h (8-9 dpf), and quantified vascular NO reactivity, vascular mural cell number, expression of a klf2a reporter, glial fibrillary acidic protein (GFAP) and transient receptor potential cation channel subfamily V member 4 (TRPV4), as well as spontaneous neuronal activation at 9 dpf, all in the optic tectum. We also assessed the effect on light/dark preference and locomotory characteristics during free-swimming studies. We find that glucose exposure significantly reduced NO reactivity, klf2a reporter expression, vascular mural cell number and TRPV4 expression, while significantly increasing spontaneous neuronal activation and GFAP expression (all in the optic tectum). Furthermore, when we examined larval behaviour, we found that glucose exposure significantly altered light/dark preference and high and low speed locomotion while in light. Co-treatment with SNP reversed all these molecular and behavioural effects of glucose exposure. Our findings comprehensively describe the negative effects of glucose exposure on the vascular anatomy, molecular phenotype and function of the optic tectum, and on whole-organism behaviour. We also show that SNP or other NO donors may represent a therapeutic strategy to ameliorate the complications of diabetes on the neurovascular unit.This article has an associated First Person interview with the first author of the paper.

Neuroendocrine modulation of predator avoidance/prey capture tradeoffs: Role of tectal NPY2R receptors.

The optic tectum rapidly inhibits food intake when a visual threat is present. Anatomical and electrophysiological evidence support a role for neuropeptide Y (NPY), originating from cells in the thalamus, in the tectal inhibition of prey capture. Here we test the hypothesis that tectal NPY receptor type 2 (NPY2R) influences prey-capture and predator-avoidance responses in the African clawed frog, Xenopus laevis. We tested two questions: 1) Does tectal NPY administration decrease food intake and alter prey-capture behavior? 2) Does tectal administration of a NPY2R antagonist increase food intake, alter prey-capture behavior, and alter predator avoidance behavior? NPY microinjected bilaterally into the tecta failed to significantly alter food intake at any dose tested, although predator presence significantly reduced food intake. However, NPY differentially altered discrete components of prey capture including increasing the latency to contact food and reducing the amount of time in contact with food. These effects were blocked by the NPY2R antagonist BIIE0246. Additionally, BIIE0246 elevated food intake on its own after bilateral tectal microinjection. Furthermore, BIIE0246 reversed the reduction of food intake caused by exposure to a predator. Overall, these findings indicate that tectal NPY2R activation causes frogs to consume food more quickly, which may be adaptive in predator-rich environments. Blocking tectal NPY2R increases baseline food intake and reduces or eliminates predator-induced changes in prey capture and food intake.

Dorsal raphe nucleus 5-Hydroxytryptamine 2A receptors are critical for the organisation of panic attack-like defensive behaviour and unconditioned fear-induced antinociception elicited by the chemical stimulation of superior colliculus neurons.

Microinjections of N-methyl-d-aspartic acid (NMDA) in the midbrain tectum structures produce panic attack-like defensive behaviours, followed by an antinociceptive response. It has been suggested that fear-related defensive responses organised by brainstem neurons can be modulated by 5-hydroxytryptamine (5-HT). However, there is a shortage of studies showing the role of dorsal raphe nucleus (DRN) 5-HT2A receptors in the modulation of panic-like behaviour and fear-induced antinociception organised by the superior colliculus (SC). The purpose of this study was to investigate the participation of DRN 5-HT2A receptors in the modulation of panic attack-like behaviour and antinociception evoked by intra-SC injections of NMDA. In experiment I, the animals received microinjections of physiological saline or NMDA (6, 9 and 12 nmol) in the deep layers of the SC (dlSC). In experiment II, the most effective dose of NMDA (12 nmol) or vehicle was preceded by microinjections of vehicle or the 5-HT2A receptor selective antagonist R-96544 at different concentrations (0.5, 5 and 10 nM) in the DRN. Both proaversive and antinociceptive effects elicited by intra-dlSC injections of NMDA were attenuated by DRN pretreatment with R-96544. In addition, a morphological analysis showed that 5-HT2A receptors are present in GABAergic interneurons in the DRN. Taken together, these findings suggest that DRN 5-HT2A receptors are critical for the modulation of both panic attack-like defensive behaviour organised by SC neurons and unconditioned fear-induced antinociception. A possible interaction between serotonergic inputs, GABAergic interneurons and serotonergic outputs from the DRN was also considered.

TrkB Activation during a Critical Period Mimics the Protective Effects of Early Visual Experience on Perception and the Stability of Receptive Fields in Adult Superior Colliculus.

During a critical period in development, spontaneous and evoked retinal activity shape visual pathways in an adaptive fashion. Interestingly, spontaneous activity is sufficient for spatial refinement of visual receptive fields (RFs) in superior colliculus (SC) and visual cortex (V1), but early visual experience is necessary to maintain inhibitory synapses and stabilize RFs in adulthood (Carrasco et al., 2005, 2011; Carrasco and Pallas, 2006; Balmer and Pallas, 2015a). In V1, BDNF and its high-affinity receptor TrkB are important for development of visual acuity, inhibition, and regulation of the critical period for ocular dominance plasticity (Hanover et al., 1999; Huang et al., 1999; Gianfranceschi et al., 2003). To examine the generality of this signaling pathway for visual system plasticity, the present study examined the role of TrkB signaling during the critical period for RF refinement in SC. Activating TrkB receptors during the critical period (P33-P40) in dark reared subjects produced normally refined RFs, and blocking TrkB receptors in light-exposed animals resulted in enlarged adult RFs like those in dark reared animals. We also report here that deprivation- or TrkB blockade-induced RF enlargement in adulthood impaired fear responses to looming overhead stimuli and negatively impacted visual acuity. Thus, early TrkB activation is both necessary and sufficient to maintain visual RF refinement, robust looming responses, and visual acuity in adulthood. These findings suggest a common signaling pathway exists for the maturation of inhibition between V1 and SC.SIGNIFICANCE STATEMENT Receptive field refinement in superior colliculus differs from more commonly studied examples of critical period plasticity in visual pathways in that it does not require visual experience to occur; rather, spontaneous activity is sufficient. Maintenance of refinement beyond puberty requires a brief, early exposure to light to stabilize the lateral inhibition that shapes receptive fields. We find that TrkB activation during a critical period can substitute for visual experience in maintaining receptive field refinement into adulthood, and that this maintenance is beneficial to visual survival behaviors. Thus, as in some other types of plasticity, TrkB signaling plays a crucial role in receptive field refinement.

In vivo effect of acute exposure to interleukin-6 on the developing visual system.

Interleukin-6 (IL-6) is involved in different processes of the central nervous system. Our aims were to investigate the effect of IL-6 on retinotectal topography and on different signaling pathways. Rats were submitted to an intravitreous injection of either IL-6 (50 ng/ml) or PBS (vehicle) at postnatal day 10 (PND10). At PND11 or PND14, different groups were processed for western blot, histochemistry or immunofluorescence analysis. IL-6 treatment leads to an increase in pSTAT-3 levels in the retina and a disruption in the retinotectal topographic map, suggesting that a transient increase in interleukin-6 levels may impact neural circuitry development.

Comparing frontal eye field and superior colliculus contributions to covert spatial attention.

The causal roles of the frontal eye fields (FEF) and superior colliculus (SC) in spatial selective attention have not been directly compared. Reversible inactivation is an established method for testing causality but comparing results between FEF and SC is complicated by differences in size and morphology of the two brain regions. Here we exploited the fact that inactivation of FEF and SC also changes the metrics of saccadic eye movements, providing an independent benchmark for the strength of the causal manipulation. Using monkeys trained to covertly perform a visual motion-change detection task, we found that inactivation of either FEF or SC could cause deficits in attention task performance. However, SC-induced attention deficits were found with saccade changes half the size needed to get FEF-induced attention deficits. Thus, performance in visual attention tasks is vulnerable to loss of signals from either structure, but suppression of SC activity has a more devastating effect.

Blockade of synaptic activity in the neostriatum and activation of striatal efferent pathways produce opposite effects on panic attack-like defensive behaviours evoked by GABAergic disinhibition in the deep layers of the superior colliculus.

The dorsal periaqueductal grey matter (dPAG) and the deep layers of the superior colliculus (dlSC) have been implicated in the organisation of innate fear-related defensive behaviours. Furthermore, GABAergic neurons from the substantia nigra pars reticulata (SNpr) connected to the dlSC and dPAG receive convergent disinhibitory inputs from the caudate-putamen (CPu), comprising the neostriatum, and modulate defence responses elicited by midbrain tectum stimulation. The purpose of this work was to study the effect of either excitatory cortico-neostriatal input blockade or neostriato-nigral GABAergic disinhibitory output activation on the responsivity of GABAergic nigro-collicular tonic inhibitory pathways during the elicitation of panic attack-like defensive responses produced by bicuculline administration into the dlSC. Thus, we investigated the effects of microinjection of either the synaptic activity blocker cobalt chloride (CoCl2) or the NMDA receptor agonist N-methyl-D-aspartic acid in the CPu on the elaboration of the defensive behaviour elicited by the selective blockade of GABAA receptors in the dlSC. Our findings showed that pretreatment of the neostriatum with CoCl2 caused clear anxiolytic and panicolytic-like effects, reducing the incidence and duration of alertness and diminishing defensive immobility and explosive escape responses. On the other hand, pretreatment of the neostriatum with NMDA (40 nmol) caused a pro-aversive effect, enhancing running and jumping responses elicited by GABAergic disinhibition in the dlSC. We conclude from the data that the neostriato-nigral disinhibitory and nigro-collicular inhibitory GABAergic pathways modulate innate fear and panic attack-like responses organised by dlSC neurons.