Suppression of excitatory synaptic transmission in the centrolateral amygdala via presynaptic histamine H3 heteroreceptors.

The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.

Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus.

Hippocampal synaptic plasticity is important for learning and memory formation. Homeostatic synaptic plasticity is a specific form of synaptic plasticity that is induced upon prolonged changes in neuronal activity to maintain network homeostasis. While astrocytes are important regulators of synaptic transmission and plasticity, it is largely unclear how they interact with neurons to regulate synaptic plasticity at the circuit level. Here, we show that neuronal activity blockade selectively increases the expression and secretion of IL-33 (interleukin-33) by astrocytes in the hippocampal cornu ammonis 1 (CA1) subregion. This IL-33 stimulates an increase in excitatory synapses and neurotransmission through the activation of neuronal IL-33 receptor complex and synaptic recruitment of the scaffold protein PSD-95. We found that acute administration of tetrodotoxin in hippocampal slices or inhibition of hippocampal CA1 excitatory neurons by optogenetic manipulation increases IL-33 expression in CA1 astrocytes. Furthermore, IL-33 administration in vivo promotes the formation of functional excitatory synapses in hippocampal CA1 neurons, whereas conditional knockout of IL-33 in CA1 astrocytes decreases the number of excitatory synapses therein. Importantly, blockade of IL-33 and its receptor signaling in vivo by intracerebroventricular administration of its decoy receptor inhibits homeostatic synaptic plasticity in CA1 pyramidal neurons and impairs spatial memory formation in mice. These results collectively reveal an important role of astrocytic IL-33 in mediating the negative-feedback signaling mechanism in homeostatic synaptic plasticity, providing insights into how astrocytes maintain hippocampal network homeostasis.

Variational dimensions of cingulate cortex functional connectivity and implications in neuropsychiatric disorders.

Significant variations in brain functional connectivity exist in the healthy population, rendering the identification and characterization of their abnormalities in neuropsychiatric disorders difficult. Here, we proposed a new principal component analysis (PCA) approach to study variations in functional connectivity, focusing on major hubs of the salience network and default mode network, namely the anterior and posterior cingulate cortices. We analyzed the intersubject variability of human functional magnetic resonance imaging connectivity obtained from healthy, autistic, and schizophrenic subjects. Utilizing data from 1000 Functional Connectomes Project, COBRE, and ABIDE 1 database, we characterized the normal variations of the cingulate cortices with respect to top PCA dimensions. We showed that functional connectivity variations of the 2 cingulate cortices are constrained, in a parallel manner, by competing or cooperating interactions with different sensorimotor, associative, and limbic networks. In schizophrenic and autistic subjects, diffuse and subtle network changes along the same dimensions were found, which suggest significant behavioral implications of the variational dimensions. Furthermore, we showed that individual dynamic functional connectivity tends to fluctuate along the principal components of connectivity variations across individuals. Our results demonstrate the strength of this new approach in addressing the intrinsic variations of network connectivity in human brain and identifying their subtle changes in neuropsychiatric disorders.

Long-range monosynaptic inputs targeting apical and basal dendrites of primary motor cortex deep output neurons.

The primary motor cortex (M1) integrates various long-range signals from other brain regions for the learning and execution of goal-directed movements. How the different inputs target the distinct apical and basal dendrites of M1 pyramidal neurons is crucial in understanding the functions of M1, but the detailed connectivity pattern is still largely unknown. Here, by combining cre-dependent rabies virus tracing, layer-specific chemical retrograde tracing, optogenetic stimulation, and electrophysiological recording, we mapped all long-range monosynaptic inputs to M1 deep output neurons in layer 5 (L5) in mice. We revealed that most upstream areas innervate both dendritic compartments concurrently. These include the sensory cortices, higher motor cortices, sensory and motor thalamus, association cortices, as well as many subcortical nuclei. Furthermore, the dichotomous inputs arise mostly from spatially segregated neuronal subpopulations within an upstream nucleus, and even in the case of an individual cortical layer. Therefore, these input areas could serve as both feedforward and feedback sources albeit via different subpopulations. Taken together, our findings revealed a previously unknown and highly intricate synaptic input pattern of M1L5 neurons, which implicates that the dendritic computations carried out by these neurons during motor execution or learning are far more complicated than we currently understand.

[Changes in sensitivity of bilateral medial vestibular nuclear neurons responding to input stimuli during vestibular compensation and the underlying ionic mechanism].

Vestibular compensation is an important model for developing the prevention and intervention strategies of vestibular disorders, and investigating the plasticity of the adult central nervous system induced by peripheral injury. Medial vestibular nucleus (MVN) in brainstem is critical center for vestibular compensation. Its neuronal excitability and sensitivity have been implicated in normal function of vestibular system. Previous studies mainly focused on the changes in neuronal excitability of the MVN in lesional side of the rat model of vestibular compensation following the unilateral labyrinthectomy (UL). However, the plasticity of sensitivity of bilateral MVN neurons dynamically responding to input stimuli is still largely unknown. In the present study, by using qPCR, whole-cell patch clamp recording in acute brain slices and behavioral techniques, we observed that 6 h after UL, rats showed a significant deficit in spontaneous locomotion, and a decrease in excitability of type B neurons in the ipsilesional rather than contralesional MVN. By contrast, type B neurons in the contralesional rather than ipsilesional MVN exhibited an increase in response sensitivity to the ramp and step input current stimuli. One week after UL, both the neuronal excitability of the ipsilesional MVN and the neuronal sensitivity of the contralesional MVN recovered to the baseline, accompanied by a compensation of spontaneous locomotion. In addition, the data showed that the small conductance Ca2+-activated K+ (SK) channel involved in the regulation of type B MVN neuronal sensitivity, showed a selective decrease in expression in the contralesional MVN 6 h after UL, and returned to normal level 1 week later. Pharmacological blockage of SK channel in contralateral MVN to inhibit the UL-induced functional plasticity of SK channel significantly delayed the compensation of vestibular motor dysfunction. These results suggest that the changes in plasticity of the ipsilesional MVN neuronal excitability, together with changes in the contralesional MVN neuronal sensitivity, may both contribute to the development of vestibular symptoms as well as vestibular compensation, and SK channel may be an essential ionic mechanism responsible for the dynamic changes of MVN neuronal sensitivity during vestibular compensation.

Dopamine receptors mediate strategy abandoning via modulation of a specific prelimbic cortex-nucleus accumbens pathway in mice.

The ability to abandon old strategies and adopt new ones is essential for survival in a constantly changing environment. While previous studies suggest the importance of the prefrontal cortex and some subcortical areas in the generation of strategy-switching flexibility, the fine neural circuitry and receptor mechanisms involved are not fully understood. In this study, we showed that optogenetic excitation and inhibition of the prelimbic cortex-nucleus accumbens (NAc) pathway in the mouse respectively enhances and suppresses strategy-switching ability in a cross-modal spatial-egocentric task. This ability is dependent on an intact dopaminergic tone in the NAc, as local dopamine denervation impaired the performance of the animal in the switching of tasks. In addition, based on a brain-slice preparation obtained from Drd2-EGFP BAC transgenic mice, we demonstrated direct innervation of D2 receptor-expressing medium spiny neurons (D2-MSNs) in the NAc by prelimbic cortical neurons, which is under the regulation by presynaptic dopamine receptors. While presynaptic D1-type receptor activation enhances the glutamatergic transmission from the prelimbic cortex to D2-MSNs, D2-type receptor activation suppresses this synaptic connection. Furthermore, manipulation of this pathway by optogenetic activation or administration of a D1-type agonist or a D2-type antagonist could restore impaired task-switching flexibility in mice with local NAc dopamine depletion; this restoration is consistent with the effects of knocking down the expression of specific dopamine receptors in the pathway. Our results point to a critical role of a specific prelimbic cortex-NAc subpathway in mediating strategy abandoning, allowing the switching from one strategy to another in problem solving.

Attenuation of intermittent hypoxia-induced apoptosis and fibrosis in pulmonary tissues via suppression of ER stress activation.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with pulmonary fibrosis and endothelial apoptosis in pulmonary tissues. Chronic intermittent hypoxia (IH) is considered to be the primary player in OSA, but the mechanisms underlying its effect on pulmonary tissues are unknown. Endoplasmic reticulum (ER) stress induced by IH treatment plays an important role in accelerating the process of fibrosis and induction of apoptosis. METHODS: Mice were placed in IH chambers for 4 weeks with an oscillating oxygen (O2) concentration between 5 and 21%, cycling every 90s for 8 h daily. Mice were randomly divided into four groups: control group (normal oxygen), tauroursodeoxycholic acid (TUDCA) group (normal oxygen intraperitoneally injected with TUDCA), IH group and IH + TUDCA group. After 4 weeks, the proteins in three branch signaling pathways of ER stress, including protein kinase RNA (PKR)-like/Pancreatic ER kinase (PERK), activating transcription factor 6 (ATF-6) and inositol-requiring enzyme 1 (IRE-1), were evaluated. The cleaved caspase-3, caspase-12 and TUNNEL staining was assessed. Furthermore, the expression of transforming growth factor-ß1 (TGF-ß1) and thrombospondin-1(TSP-1), two extracellular matrix proteins that play critical role in fibrosis, were examined. Finally, Masson's trichrome staining was performed to detect the expression of collagen. RESULTS: After 4 weeks of IH treatment, the expressions of two ER stress markers, glucose regulated protein-78 (Grp78) and transcription factor C/EBP homologous protein (CHOP) were increased which was prevented by administration of the ER stress attenuator, TUDCA. The expressions of PERK, but not those of ATF-6 and IRE-1, were increased. The effects of IH were accompanied by an increased number of apoptotic cells and increased expressions of cleaved caspase-3 and caspase-12 in pulmonary tissues. In addition, histological examination suggested the presence of fibrosis after chronic IH treatment, indicated by increased expression of collagen, which was associated with the up-regulation of TGF-ß1 and TSP-1 that are known to promote fibrosis. Similarly, TUDCA could reduce the extent of fibrotic area and the expression levels of these proteins. CONCLUSIONS: It reveals the roles of ER stress, especially the PERK pathway, in IH induced apoptosis and fibrosis in pulmonary tissues that might underlie the pulmonary complications observed in OSA.

Cystathionine ß-synthase is required for body iron homeostasis.

Cystathionine ß-synthase (CBS) catalyzes the transsulfuration pathway and contributes, among other functions, to the generation of hydrogen sulfide. In view of the exceptionally high expression of CBS in the liver and the common interleukin-6 pathway used in the regulatory systems of hydrogen sulfide and hepcidin, we speculate that CBS is involved in body iron homeostasis. We found that CBS knockout (CBS-/- ) mice exhibited anemia and a significant increase in iron content in the serum, liver, spleen, and heart, along with severe damage to the liver, displaying a hemochromatosis-like phenotype. A high level of hepatic and serum hepcidin was also found. A major cause of the systemic iron overload is the reduced iron usage due to suppressed erythropoiesis, which is consistent with an increase in interleukin-6 and reduced expression of erythropoietin. Importantly, in the liver, absence of CBS caused both a reduction in the transcriptional factor nuclear factor erythroid 2-related factor-2 and an up-regulation of hepcidin that led to a decrease in the iron export protein ferroportin 1. The resulting suppression of iron export exacerbates iron retention, causing damage to hepatocytes. Finally, administration of CBS-overexpressing adenovirus into CBS mutant mice could partially reverse the iron-related phenotype. CONCLUSION: Our findings point to a critical role of CBS in iron homeostasis of the body, and the liver in particular; it is likely that a hemochromatosis-like phenotype in patients can be induced by aberration not only in the expression of key molecules in the hepcidin pathway but also of those related to CBS. (Hepatology 2018;67:21-35).

A binding site outside the canonical PDZ domain determines the specific interaction between Shank and SAPAP and their function.

Shank and SAPAP (synapse-associated protein 90/postsynaptic density-95-associated protein) are two highly abundant scaffold proteins that directly interact with each other to regulate excitatory synapse development and plasticity. Mutations of SAPAP, but not other reported Shank PDZ domain binders, share a significant overlap on behavioral abnormalities with the mutations of Shank both in patients and in animal models. The molecular mechanism governing the exquisite specificity of the Shank/SAPAP interaction is not clear, however. Here we report that a sequence preceding the canonical PDZ domain of Shank, together with the elongated PDZ BC loop, form another binding site for a sequence upstream of the SAPAP PDZ-binding motif, leading to a several hundred-fold increase in the affinity of the Shank/SAPAP interaction. We provide evidence that the specific interaction afforded by this newly identified site is required for Shank synaptic targeting and the Shank-induced synaptic activity increase. Our study provides a molecular explanation of how Shank and SAPAP dosage changes due to their gene copy number variations can contribute to different psychiatric disorders.

Long-range projections coordinate distributed brain-wide neural activity with a specific spatiotemporal profile.

One challenge in contemporary neuroscience is to achieve an integrated understanding of the large-scale brain-wide interactions, particularly the spatiotemporal patterns of neural activity that give rise to functions and behavior. At present, little is known about the spatiotemporal properties of long-range neuronal networks. We examined brain-wide neural activity patterns elicited by stimulating ventral posteromedial (VPM) thalamo-cortical excitatory neurons through combined optogenetic stimulation and functional MRI (fMRI). We detected robust optogenetically evoked fMRI activation bilaterally in primary visual, somatosensory, and auditory cortices at low (1 Hz) but not high frequencies (5-40 Hz). Subsequent electrophysiological recordings indicated interactions over long temporal windows across thalamo-cortical, cortico-cortical, and interhemispheric callosal projections at low frequencies. We further observed enhanced visually evoked fMRI activation during and after VPM stimulation in the superior colliculus, indicating that visual processing was subcortically modulated by low-frequency activity originating from VPM. Stimulating posteromedial complex thalamo-cortical excitatory neurons also evoked brain-wide blood-oxygenation-level-dependent activation, although with a distinct spatiotemporal profile. Our results directly demonstrate that low-frequency activity governs large-scale, brain-wide connectivity and interactions through long-range excitatory projections to coordinate the functional integration of remote brain regions. This low-frequency phenomenon contributes to the neural basis of long-range functional connectivity as measured by resting-state fMRI.

Platelets mediate protective neuroinflammation and promote neuronal plasticity at the site of neuronal injury.

It is generally accepted that inflammation within the CNS contributes to neurodegeneration after traumatic brain injury (TBI), but it is not clear how inflammation is initiated in the absence of infection and whether this neuroinflammation is predominantly beneficial or detrimental. We have previously found that brain-enriched glycosphingolipids within neuronal lipid rafts (NLR) induced platelet degranulation and secretion of neurotransmitters and pro-inflammatory factors. In the present study, we compared TBI-induced inflammation and neurodegeneration in wild-type vs. St3gal5 deficient (ST3-/-) mice that lack major CNS-specific glycosphingolipids. After TBI, microglial activation and CNS macrophage infiltration were substantially reduced in ST3-/- animals. However, ST3-/- mice had a larger area of CNS damage with marked neuronal/axonal loss. The interaction of platelets with NLR stimulated neurite growth, increased the number of PSD95-positive dendritic spines, and intensified neuronal activity. Adoptive transfer and blocking experiments provide further that platelet-derived serotonin and platelet activating factor plays a key role in the regulation of sterile neuroinflammation, hemorrhage and neuronal plasticity after TBI.

Differential interaction between iron and mutant alpha-synuclein causes distinctive Parkinsonian phenotypes in Drosophila.

Alpha-synuclein aggregation is the central hallmark of both sporadic and familial Parkinson's disease (PD). Patients with different PD-causing genetic defects of alpha-synuclein usually show distinctive clinical features that are atypical to sporadic PD. Iron accumulation is invariably found in PD. Recent studies showed that mutant and wild-type alpha-synuclein may have differential interaction with iron and mutant alpha-synuclein toxicity could be preferentially exacerbated by iron. We hence hypothesized that iron overload could selectively influence mutant alpha-synuclein toxicity and disease phenotypes. To test the hypothesis, we investigated if Drosophila melanogaster over-expressing A53T, A30P, and wild-type (WT) alpha-synuclein have different responses to iron treatment. We showed that iron treatment induced similar reduction of survival rate in all flies but induced a more severe motor decline in A53T and A30P mutant alpha-synuclein expressing flies, suggesting interaction between mutant alpha-synuclein and iron. Although no significant difference in total head iron content was found among these flies, we demonstrated that iron treatment induced selective DA neuron loss in motor-related PPM3 cluster only in the flies that express A53T and A30P mutant alpha-synuclein. We provided the first in vivo evidence that iron overload could induce distinctive neuropathology and disease phenotypes in mutant but not WT alpha-synuclein expressing flies, providing insights to the cause of clinical features selectively exhibited by mutant alpha-synuclein carriers.

The multi-level impact of chronic intermittent hypoxia on central auditory processing.

During hypoxia, the tissues do not obtain adequate oxygen. Chronic hypoxia can lead to many health problems. A relatively common cause of chronic hypoxia is sleep apnea. Sleep apnea is a sleep breathing disorder that affects 3-7% of the population. During sleep, the patient's breathing starts and stops. This can lead to hypertension, attention deficits, and hearing disorders. In this study, we apply an established chronic intermittent hypoxemia (CIH) model of sleep apnea to study its impact on auditory processing. Adult rats were reared for seven days during sleeping hours in a gas chamber with oxygen level cycled between 10% and 21% (normal atmosphere) every 90s. During awake hours, the subjects were housed in standard conditions with normal atmosphere. CIH treatment significantly reduces arterial oxygen partial pressure and oxygen saturation during sleeping hours (relative to controls). After treatment, subjects underwent functional magnetic resonance imaging (fMRI) with broadband sound stimulation. Responses are observed in major auditory centers in all subjects, including the auditory cortex (AC) and auditory midbrain. fMRI signals from the AC are statistically significantly increased after CIH by 0.13% in the contralateral hemisphere and 0.10% in the ipsilateral hemisphere. In contrast, signals from the lateral lemniscus of the midbrain are significantly reduced by 0.39%. Signals from the neighboring inferior colliculus of the midbrain are relatively unaffected. Chronic hypoxia affects multiple levels of the auditory system and these changes are likely related to hearing disorders associated with sleep apnea.

5-HT3a Receptors Modulate Hippocampal Gamma Oscillations by Regulating Synchrony of Parvalbumin-Positive Interneurons.

Gamma-frequency oscillatory activity plays an important role in information integration across brain areas. Disruption in gamma oscillations is implicated in cognitive impairments in psychiatric disorders, and 5-HT3 receptors (5-HT3Rs) are suggested as therapeutic targets for cognitive dysfunction in psychiatric disorders. Using a 5-HT3aR-EGFP transgenic mouse line and inducing gamma oscillations by carbachol in hippocampal slices, we show that activation of 5-HT3aRs, which are exclusively expressed in cholecystokinin (CCK)-containing interneurons, selectively suppressed and desynchronized firings in these interneurons by enhancing spike-frequency accommodation in a small conductance potassium (SK)-channel-dependent manner. Parvalbumin-positive interneurons therefore received diminished inhibitory input leading to increased but desynchronized firings of PV cells. As a consequence, the firing of pyramidal neurons was desynchronized and gamma oscillations were impaired. These effects were independent of 5-HT3aR-mediated CCK release. Our results therefore revealed an important role of 5-HT3aRs in gamma oscillations and identified a novel crosstalk among different types of interneurons for regulation of network oscillations. The functional link between 5-HT3aR and gamma oscillations may have implications for understanding the cognitive impairments in psychiatric disorders.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate firing of globus pallidus neurons in vivo.

The globus pallidus plays a significant role in motor control under both health and pathological states. Recent studies have revealed that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels occupy a critical position in globus pallidus pacemaking activity. Morphological studies have shown the expression of HCN channels in the globus pallidus. To investigate the in vivo effects of HCN channels in the globus pallidus, extracellular recordings and behavioral tests were performed in the present study. In normal rats, micro-pressure ejection of 0.05mM ZD7288, the selective HCN channel blocker, decreased the frequency of spontaneous firing in 21 out of the 40 pallidal neurons. The average decrease was 50.4±5.4%. Interestingly, in another 18 out of the 40 pallidal neurons, ZD7288 increased the firing rate by 137.1±27.6%. Similar bidirectional modulation on the firing rate was observed by a higher concentration of ZD7288 (0.5mM) as well as another HCN channel blocker, CsCl. Furthermore, activation of HCN channels by 8-Br-cAMP increased the firing rate by 63.0±9.3% in 15 out of the 25 pallidal neurons and decreased the firing rate by 46.9±9.4% in another 8 out of the 25 pallidal neurons. Further experiments revealed that modulation of glutamatergic but not GABAergic transmission may be involved in ZD7288-induced increase in firing rate. Consistent with electrophysiological results, further studies revealed that modulation of HCN channels also had bidirectional effects on behavior. Taken together, the present studies suggest that HCN channels may modulate the activity of pallidal neurons by different pathways in vivo.

Cdk5-dependent Mst3 phosphorylation and activity regulate neuronal migration through RhoA inhibition.

The radial migration of newborn neurons is critical for the lamination of the cerebral cortex. Proper neuronal migration requires precise and rapid reorganization of the actin and microtubule cytoskeleton. However, the underlying signaling mechanisms controlling cytoskeletal reorganization are not well understood. Here, we show that Mst3, a serine/threonine kinase highly expressed in the developing mouse brain, is essential for radial neuronal migration and final neuronal positioning in the developing mouse neocortex. Mst3 silencing by in utero electroporation perturbed the multipolar-to-bipolar transition of migrating neurons and significantly retards radial migration. Although the kinase activity of Mst3 is essential for its functions in neuronal morphogenesis and migration, it is regulated via its phosphorylation at Ser79 by a serine/threonine kinase, cyclin-dependent kinase 5 (Cdk5). Our results show that Mst3 regulates neuronal migration through modulating the activity of RhoA, a Rho-GTPase critical for actin cytoskeletal reorganization. Mst3 phosphorylates RhoA at Ser26, thereby negatively regulating the GTPase activity of RhoA. Importantly, RhoA knockdown successfully rescues neuronal migration defect in Mst3-knockdown cortices. Our findings collectively suggest that Cdk5-Mst3 signaling regulates neuronal migration via RhoA-dependent actin dynamics.

Injured adult retinal axons with Pten and Socs3 co-deletion reform active synapses with suprachiasmatic neurons.

Despite advances in promoting axonal regeneration after adult central nervous system injury, elicitation of a large number of lesion-passing axons reform active synaptic connections with natural target neurons remains limited. By deleting both Pten and Socs3 in retinal ganglion cells, we report that optic nerve axons after prechiasm lesion robustly reinnervate the hypothalamus, form new synapses with neurons in the suprachiasmatic nucleus (SCN), and re-integrate with the existing circuitry. Photic or electric stimulation of the retinal axons induces neuronal response in SCN. However both the innervation pattern and evoked responses are not completely restored by the regenerating axons, suggesting that combining with other strategies is necessary to overcome the defective rewiring. Our results support that boosting the intrinsic growth capacity in injured neurons promotes axonal reinnervation and rewiring.

Fast 3-D temporal focusing microscopy using an electrically tunable lens.

In this paper, we present a 3-D temporal focusing microscope based on an electrically tunable lens (ETL) and a femtosecond regenerative laser amplifier. The focus-tunable lens provides a fast and compact way to perform non-mechanical z-scanning and resolves the blurry image issue compared with GVD-based z-scanning methods. The optical performance of the temporal focusing system, including z-scanning characteristics, the associated the magnification variation, and the lateral and axial resolution, has been studied and characterized using calibrated Rhodamine-6G thin film sample, fluorescent beads, and pollen samples. Lastly, we demonstrate the optical cross-sectioning and z-scanning capability with an in vivo experiment, where Ca(2+) imaging of neurons in GaCamp6 labeled zebrafish was performed.

Drosophila models for studying iron-related neurodegenerative diseases.

In recent years, iron has been regarded as a common pathological feature of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Friedreich's ataxia (FRDA). A number of genes involved in iron transport, storage and regulation have been found associated with initiation and progression of neurodegeneration. However, whether iron abnormalities represent a primary or secondary event still remains unknown. Due to the limitation in transgenic rodent model construction and transfection systems, the progress in unraveling the pathogenic role of different iron-related proteins in neurodegenerative diseases has been slow. Drosophila melanogaster, a simple organism which has a shorter lifespan and smaller genome with many conserved genes, and captures many features of human nervous system and neurodegeneration, may help speed up the progress. The characteristics that spatial- and temporal-specific transgenic Drosophila can be easily constructed and raised in large quantity with phenotype easily determined turn Drosophila into an excellent in vivo genetic system for screening iron-related modifiers in different neurodegenerative conditions and hence provide a better picture about the pathogenic contribution of different iron-related protein abnormalities. It is believed that identification of important iron-related genes that can largely stop or even reverse degenerative process in Drosophila models may lead to development of novel therapeutic strategies against neurodegenerative diseases.

Disparate processing of numerosity and associated continuous magnitudes in rats.

The studies of number sense in different species are severely hampered by the inevitable entanglement of non-numerical attributes inherent in nonsymbolic stimuli representing numerosity, resulting in contrasting theories of numerosity processing. Here, we developed an algorithm and associated analytical methods to generate stimuli that not only minimized the impact of non-numerical magnitudes in numerosity perception but also allowed their quantification. We trained number-naïve rats with these stimuli as sound pulses representing two or three numbers and demonstrated that their numerical discrimination ability mainly relied on numerosity. Also, studying the learning process revealed that rats used numerosity before using magnitudes for choices. This numerical processing could be impaired specifically by silencing the posterior parietal cortex. Furthermore, modeling this capacity by neural networks shed light on the separation of numerosity and magnitudes extraction. Our study helps dissect the relationship between magnitude and numerosity processing, and the above different findings together affirm the independent existence of innate number and magnitudes sense in rats.