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Zika virus' neural tropism causes significant neural pathology, particularly in developing fetuses. One of the consistent findings from humans and animal models is that prenatal exposure to Zika virus (ZIKV) causes pathology in the eyes and visual pathways of the brain, although the extent to which this pathology persists over development is not clear. In the present report, we build upon our previous work which demonstrated that full-term rhesus monkey ( Macaca mulatta ) fetuses who were exposed to ZIKV early in gestation had significant pathological abnormalities to the organization of the lateral geniculate nucleus (LGN), a major hub of the visual network. The objective of the present work was to replicate those LGN findings and determine whether such pathology persisted across childhood development. We carried out histological analyses of the LGNs of two juvenile rhesus monkeys who were prenatally exposed to ZIKV and two age-matched controls. Pregnant rhesus monkeys were infected with ZIKV via the intravenous and intra-amniotic routes and tracked across development. Following sacrifice and perfusion, brains were subjected to quantitative neuroanatomical analyses with a focus on the size and structure of the LGN and its composite layers. Early fetal ZIKV exposure resulted in developmental abnormalities within the brains' visual pathway: specifically disorganization, blending of layers, laminar discontinuities, and regions of low cell density within the LGN. These abnormalities were not observed in the control animals. Our findings demonstrate that the ZIKV's damage to the LGN that occurs during fetal development persists into childhood.

Cortical responses to visual stimuli are believed to rely on the geniculo-striate pathway. However, recent work has challenged this notion by showing that responses in the postrhinal cortex (POR), a visual cortical area, instead depend on the tecto-thalamic pathway, which conveys visual information to the cortex via the superior colliculus (SC). Does PORs SC-dependence point to a wider system of tecto-thalamic cortical visual areas? What information might this system extract from the visual world? We discovered multiple mouse cortical areas whose visual responses rely on SC, with the most lateral showing the strongest SC-dependence. This system is driven by a genetically defined cell type that connects the SC to the pulvinar thalamic nucleus. Finally, we show that SC-dependent cortices distinguish self-generated from externally generated visual motion. Hence, lateral visual areas comprise a system that relies on the tecto-thalamic pathway and contributes to processing visual motion as animals move through the environment.

Before visual information from the retina reaches primary visual cortex (V1), it is dynamically filtered by the lateral geniculate nucleus (LGN) of the thalamus, the first location within the visual hierarchy at which nonretinal structures can significantly influence visual processing. To explore the form and dynamics of geniculate filtering we used data from monosynpatically connected pairs of retinal ganglion cells (RGCs) and LGN relay cells in the cat that, under anesthetized conditions, were stimulated with binary white noise and/or drifting sine-wave gratings to train models of increasing complexity to predict which RGC spikes were relayed to cortex, what we call "relay status." In addition, we analyze and compare a smaller dataset recorded in the awake state to assess how anesthesia might influence our results. Consistent with previous work, we find that the preceding retinal interspike interval (ISI) is the primary determinate of relay status with only modest contributions from longer patterns of retinal spikes. Including the prior activity of the LGN cell further improved model predictions, primarily by indicating epochs of geniculate burst activity in recordings made under anesthesia, and by allowing the model to capture gain control-like behavior within the awake LGN. Using the same modeling framework, we further demonstrate that the form of geniculate filtering changes according to the level of activity within the early visual circuit under certain stimulus conditions. This finding suggests a candidate mechanism by which a stimulus specific form of gain control may operate within the LGN.

Objective(s): Diabetes during gestation is one of the most common pregnancy complications and has adverse effects on offspring, including a negative impact on the offspring’s central nervous system (CNS). Diabetes is a metabolic disease associated with visual impairment. Due to the importance of the lateral geniculate body (LGB) in the visual pathway, the present study examined the effect of maternal diabetes on the expression of gamma-aminobutyric acid (GABAAα1 and GABAB1) and metabotropic Glutamate (mGlu2) receptors in the LGB of male neonates of diabetic rats.Materials and Methods: Diabetes was induced in female adult rats by a single intraperitoneal dose of streptozotocin (STZ) 65 (mg/kg). In the Insulin-treated diabetic rats, diabetes was controlled by subcutaneous NPH-insulin injection daily. After mating and delivery, male offspring were killed by carbon dioxide gas inhalation at P0, P7, and P14 (postnatal days 0, 7, and 14). The expression of GABAAα1, GABAB1, and mGluR2 in the LGB of male neonates was determined using the immunohistochemistry (IHC) method.Results: The expression of GABAAα1 and GABAB1 was significantly reduced, whereas the expression of mGluR2 was markedly increased in the diabetic group compared with the control and insulin-treated groups at P0, P7, and P14.Conclusion: The results of the present study showed that induction of diabetes altered the expression of GABAAα1, GABAB1, and mGluR2 in the LGB of male neonates born to diabetic rats at P0, P7, and P14. Moreover, insulin treatment could reverse these effects of diabetes.

How many thalamic neurons converge onto a cortical cell? This is an important question, because the organization of thalamocortical projections can influence the cortical architecture.1,2 Here, we estimate the degree of thalamocortical convergence in primary visual cortex by taking advantage of the cortical expansion-neurons within a restricted volume in primary visual cortex have overlapping receptive fields driven by a smaller set of inputs from the lateral geniculate nucleus.3-5 Under these conditions, the measurements of cortical receptive fields in a population can be used to infer the receptive fields of their geniculate inputs and the weights of their projections using non-negative matrix factorization.6 The analysis reveals sparse connectivity,7 where a handful (~2-6) of thalamic inputs account for 90% of the total synaptic weight to a cortical neuron. Together with previous findings,8 these results paint a picture consistent with the idea that convergence of a few inputs partly determine the retinotopy and tuning properties of cortical cells.8-13.

Objective(s): Diabetes during gestation is one of the most common pregnancy complications and has adverse effects on offspring, including a negative impact on the offspring's central nervous system (CNS). Diabetes is a metabolic disease associated with visual impairment. Due to the importance of the lateral geniculate body (LGB) in the visual pathway, the present study examined the effect of maternal diabetes on the expression of gamma-aminobutyric acid (GABAAa1 and GABAB1) and metabotropic Glutamate (mGlu2) receptors in the LGB of male neonates of diabetic rats. Materials and Methods: Diabetes was induced in female adult rats by a single intraperitoneal dose of streptozotocin (STZ) 65 (mg/kg). In the Insulin-treated diabetic rats, diabetes was controlled by subcutaneous NPH-insulin injection daily. After mating and delivery, male offspring were killed by carbon dioxide gas inhalation at P0, P7, and P14 (postnatal days 0, 7, and 14). The expression of GABAAa1, GABAB1, and mGluR2 in the LGB of male neonates was determined using the immunohistochemistry (IHC) method. Results: The expression of GABAAa1 and GABAB1 was significantly reduced, whereas the expression of mGluR2 was markedly increased in the diabetic group compared with the control and insulin-treated groups at P0, P7, and P14. Conclusion: The results of the present study showed that induction of diabetes altered the expression of GABAAa1, GABAB1, and mGluR2 in the LGB of male neonates born to diabetic rats at P0, P7, and P14. Moreover, insulin treatment could reverse these effects of diabetes. [ABSTRACT FROM AUTHOR]

Which neural circuits undergo synaptic changes when an animal learns? Although it is widely accepted that changes in synaptic strength underlie many forms of learning and memory, it remains challenging to connect changes in synaptic strength at specific neural pathways to specific behaviors and memories. Here we introduce SYNPLA (synaptic proximity ligation assay), a synapse-specific, high-throughput, and potentially brain-wide method capable of detecting circuit-specific learning-induced synaptic plasticity.

Study of the neural deficits caused by mismatched binocular vision in early childhood has predominantly focused on circuits in the primary visual cortex (V1). Recent evidence has revealed that neurons in mouse dorsolateral geniculate nucleus (dLGN) can undergo rapid ocular dominance plasticity following monocular deprivation (MD). It remains unclear, however, whether the long-lasting deficits attributed to MD during the critical period originate in the thalamus. Using in vivo two-photon Ca2+ imaging of dLGN afferents in superficial layers of V1 in female and male mice, we demonstrate that 14 d MD during the critical period leads to a chronic loss of binocular dLGN inputs while sparing response strength and spatial acuity. Importantly, MD leads to profoundly mismatched visual tuning properties in remaining binocular dLGN afferents. Furthermore, MD impairs binocular modulation, reducing facilitation of responses of both binocular and monocular dLGN inputs during binocular viewing. As predicted by our findings in thalamic inputs, Ca2+ imaging from V1 neurons revealed spared spatial acuity but impaired binocularity in L4 neurons. V1 L2/3 neurons in contrast displayed deficits in both binocularity and spatial acuity. Our data demonstrate that critical-period MD produces long-lasting disruptions in binocular integration beginning in early binocular circuits in dLGN, whereas spatial acuity deficits first arise from circuits further downstream in V1. Our findings indicate that the development of normal binocular vision and spatial acuity depend upon experience-dependent refinement of distinct stages in the mammalian visual system.SIGNIFICANCE STATEMENT Abnormal binocular vision and reduced acuity are hallmarks of amblyopia, a disorder that affects 2%-5% of the population. It is widely thought that the neural deficits underlying amblyopia begin in the circuits of primary visual cortex. Using in vivo two-photon calcium imaging of thalamocortical axons in mice, we show that depriving one eye of input during a critical period in development chronically impairs binocular integration in thalamic inputs to primary visual cortex. In contrast, visual acuity is spared in thalamic inputs. These findings shed new light on the role for developmental mechanisms in the thalamus in establishing binocular vision and may have critical implications for amblyopia.

Retinal signals are transmitted to cortex via neurons in the lateral geniculate nucleus (LGN), where they are processed in burst or tonic response mode. Burst mode occurs when LGN neurons are sufficiently hyperpolarized for T-type Ca2+ channels to deinactivate, allowing them to open in response to depolarization, which can trigger a high-frequency sequence of Na+-based spikes (i.e., burst). In contrast, T-type channels are inactivated during tonic mode and do not contribute to spiking. Although burst mode is commonly associated with sleep and the disruption of retinogeniculate communication, bursts can also be triggered by visual stimulation, thereby transforming the retinal signals relayed to the cortex. To determine how burst mode affects retinogeniculate communication, we made recordings from monosynaptically connected retinal ganglion cells and LGN neurons in male/female cats during visual stimulation. Our results reveal a robust augmentation of retinal signals within the LGN during burst mode. Specifically, retinal spikes were more effective and often triggered multiple LGN spikes during periods likely to have increased T-type Ca2+ channel activity. Consistent with the biophysical properties of T-type Ca2+ channels, analysis revealed that effect magnitude was correlated with the duration of the preceding thalamic interspike interval and occurred even in the absence of classically defined bursts. Importantly, the augmentation of geniculate responses to retinal input was not associated with a degradation of visual signals. Together, these results indicate a graded nature of response mode and suggest that, under certain conditions, bursts facilitate the transmission of visual information to the cortex by amplifying retinal signals.SIGNIFICANCE STATEMENT The thalamus is the gateway for retinal information traveling to the cortex. The lateral geniculate nucleus, like all thalamic nuclei, has two classically defined categories of spikes-tonic and burst-that differ in their underlying cellular mechanisms. Here we compare retinogeniculate communication during burst and tonic response modes. Our results show that retinogeniculate communication is enhanced during burst mode and visually evoked thalamic bursts, thereby augmenting retinal signals transmitted to cortex. Further, our results demonstrate that the influence of burst mode on retinogeniculate communication is graded and can be measured even in the absence of classically defined thalamic bursts.

Visual information processed in the retina is transmitted to primary visual cortex via relay cells in the lateral geniculate nucleus (LGN) of the dorsal thalamus. Although retinal ganglion cells are the primary source of driving input to LGN neurons, not all retinal spikes are transmitted to the cortex. Here, we investigate the relationship between stimulus contrast and retinogeniculate communication and test the hypothesis that both the time course and strength of retinogeniculate interactions are dynamic and dependent on stimulus contrast. By simultaneously recording the spiking activity of synaptically connected retinal ganglion cells and LGN neurons in the cat, we show that the temporal window for retinogeniculate integration and the effectiveness of individual retinal spikes are inversely proportional to stimulus contrast. This finding provides a mechanistic understanding for the phenomenon of augmented contrast gain control in the LGN-a nonlinear receptive field property of LGN neurons whereby response gain during low-contrast stimulation is enhanced relative to response gain during high-contrast stimulation. In addition, these results support the view that network interactions beyond the retina play an essential role in transforming visual signals en route from retina to cortex.

The basal forebrain provides cholinergic inputs to primary visual cortex (V1) that play a key modulatory role on visual function. While basal forebrain afferents terminate in the infragranular layers of V1, acetylcholine is delivered to more superficial layers through volume transmission. Nevertheless, direct synaptic contact in deep layers 5 and 6 may provide a more immediate effect on V1 modulation. Using helper viruses with cell type specific promoters to target retrograde infection of pseudotyped and genetically modified rabies virus evidence was found for direct synaptic input onto V1 inhibitory neurons. These inputs were similar in number to geniculocortical inputs and, therefore, considered robust. In contrast, while clear evidence for dorsal lateral geniculate nucleus input to V1 excitatory neurons was found, there was no evidence of direct synaptic input from the basal forebrain. These results suggest a direct and more immediate influence of the basal forebrain on local V1 inhibition.

Retinal waves are bursts of correlated activity that occur prior to eye opening and provide a critical source of activity that drives the refinement of retinofugal projections. Retinal waves are thought to be initiated spontaneously with their spatiotemporal features dictated by immature neural circuits. Here we demonstrate that, during the second postnatal week in mice, changes in light intensity dictate where and when a subset of retinal waves are triggered via activation of conventional photoreceptors. Propagation properties of triggered waves are indistinguishable from spontaneous waves, indicating that they are activating the same retinal circuits. Using whole-brain imaging techniques, we demonstrate that light deprivation prior to eye opening diminishes eye-specific segregation of the retinal projections to the dorsolateral geniculate nucleus of the thalamus, but not other retinal targets. These data indicate that light that passes through the closed eyelids plays a critical role in the development of the image-forming visual system.

BackgroundHomeodomain (HD) transcription factor (TF) NKX2-1 critical for the regional specification of the medial ganglionic eminence (MGE) as well as promoting the GABAergic and cholinergic neuron fates via the induction of TFs such as LHX6 and LHX8. NKX2-1 defines MGE regional identity in large part through transcriptional repression, while specification and maturation of GABAergic and cholinergic fates is mediated in part by transcriptional activation via TFs such as LHX6 and LHX8. Here we analyze the signaling and TF pathways, downstream of NKX2-1, required for GABAergic and cholinergic neuron fate maturation.MethodsDifferential ChIP-seq analysis was used to identify regulatory elements (REs) where chromatin state was sensitive to change in the Nkx2-1cKO MGE at embryonic day (E) 13.5. TF motifs in the REs were identified using RSAT. CRISPR-mediated genome editing was used to generate enhancer knockouts. Differential gene expression in these knockouts was analyzed through RT-qPCR and in situ hybridization. Functional analysis of motifs within hs623 was analyzed via site directed mutagenesis and reporter assays in primary MGE cultures.ResultsWe identified 4782 activating REs (aREs) and 6391 repressing REs (rREs) in the Nkx2-1 conditional knockout (Nkx2-1cKO) MGE. aREs are associated with basic-Helix-Loop-Helix (bHLH) TFs. Deletion of hs623, an intragenic Tcf12 aRE, caused a reduction of Tcf12 expression in the sub-ventricular zone (SVZ) and mantle zone (MZ) of the MGE. Mutation of LHX, SOX and octamers, within hs623, caused a reduction of hs623 activity in MGE primary cultures.ConclusionsTcf12 expression in the SVZ of the MGE is mediated through aRE hs623. The activity of hs623 is dependent on LHX6, SOX and octamers. Thus, maintaining the expression of Tcf12 in the SVZ involves on TF pathways parallel and genetically downstream of NKX2-1.

Titi monkeys are arboreal, diurnal New World monkeys whose ancestors were the first surviving branch of the New World radiation. In the current study, we use cytoarchitectonic and immunohistochemical characteristics to compare titi monkey subcortical structures associated with visual processing with those of other well-studied primates. Our goal was to appreciate features that are similar across all New World monkeys, and primates in general, versus those features that are unique to titi monkeys and other primate taxa. We examined tissue stained for Nissl substance, cytochrome oxidase (CO), acetylcholinesterase (AChE), calbindin (Cb), parvalbumin (Pv), and vesicular glutamate transporter 2 (VGLUT2) to characterize the superior colliculus, lateral geniculate nucleus, and visual pulvinar. This is the first study to characterize VGLUT2 in multiple subcortical structures of any New World monkey. Our results from tissue processed for VGLUT2, in combination with other histological stains, revealed distinct features of subcortical structures that are similar to other primates, but also some features that are slightly modified compared to other New World monkeys and other primates. These included subdivisions of the inferior pulvinar, sublamina within the stratum griseum superficiale (SGS) of the superior colliculus, and specific koniocellular layers within the lateral geniculate nucleus. Compared to other New World primates, many features of the subcortical structures that we examined in titi monkeys were most similar to those in owl monkeys and marmosets, with the lateral geniculate nucleus consisting of two main parvocellular layers and two magnocellular layers separated by interlaminar zones or koniocellular layers.

Neural circuits and the cells that comprise them undergo developmental changes in the spatial organization of their connections and in their temporal response properties. Within the lateral geniculate nucleus (LGN) of the dorsal thalamus, these changes have pronounced effects on the spatiotemporal receptive fields (STRFs) of neurons. An open and unresolved question is how STRF maturation affects stimulus-evoked correlated activity between pairs of LGN neurons during development. This is an important question to answer because stimulus-evoked correlated activity likely plays a role in establishing the specificity of thalamocortical connectivity and the receptive fields (RFs) of postsynaptic cortical neurons. Using multielectrode recording methods and white noise stimuli, we recorded neural activity from ensembles of LGN neurons in cats across early development. As expected, there was a progressive maturation of the spatial and temporal properties of visual responses. Using drifting bar stimuli and cross-correlation analysis, we also determined the orientation-tuning bandwidth of correlated activity between pairs of LGN neurons at different stages of development (Sillito and Jones, 2002; Andolina et al., 2007; Stanley et al., 2012; Kelly et al., 2014). Despite the larger RFs and slower responses of immature LGN neurons compared with mature neurons, our results show that correlated activity in the LGN was as tightly tuned for orientation early in development as it was in the adult. Closer examination revealed this age-invariant orientation tuning of correlated activity likely involves cellular mechanisms related to spike fatigue in young animals and a progressive decrease in response latency with development.SIGNIFICANCE STATEMENT Orientation tuning is a fundamental property of neurons in primary visual cortex. An important and unresolved question is how orientation tuning emerges during brain development. This study explores a potential mechanism for the establishment of orientation tuning based on correlated activity patterns among ensembles of maturing neurons in the lateral geniculate nucleus (LGN) of the thalamus. Results show that correlated activity between pairs of LGN neurons is more tightly tuned than predictions based simply on receptive field size, indicating that correlated activity has the properties needed to play an important role in the development of geniculocortical circuits and the emergence of cortical orientation tuning.

Aberrant connectivity is believed to contribute to the pathophysiology of autism spectrum disorder (ASD). Recent neuroimaging studies have increasingly identified such impairments in patients with ASD, including alterations in sensory systems. However, the cellular substrates and molecular underpinnings of disrupted connectivity remain poorly understood. Utilizing eye-specific segregation in the dorsal lateral geniculate nucleus (dLGN) as a model system, we investigated the formation and refinement of precise patterning of synaptic connections in the BTBR T + tf/J (BTBR) mouse model of ASD. We found that at the neonatal stage, the shape of the dLGN occupied by retinal afferents was altered in the BTBR group compared to C57BL/6J (B6) animals. Notably, the degree of overlap between the ipsi- and contralateral afferents was significantly greater in the BTBR mice. Moreover, these abnormalities continued into mature stage in the BTBR animals, suggesting persistent deficits rather than delayed maturation of axonal refinement. Together, these results indicate disrupted connectivity at the synaptic patterning level in the BTBR mice, suggesting that in general, altered neural circuitry may contribute to autistic behaviours seen in this animal model. In addition, these data are consistent with the notion that lower-level, primary processing mechanisms contribute to altered visual perception in ASD. Autism Res 2017, 10: 212-223. © 2016 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.

Extraclassical surround suppression is a prominent receptive field property of neurons in the lateral geniculate nucleus (LGN) of the dorsal thalamus, influencing stimulus size tuning, response gain control, and temporal features of visual responses. Despite evidence for the involvement of both retinal and non-retinal circuits in the generation of extraclassical suppression, we lack an understanding of the relative roles played by these pathways and how they interact during visual stimulation. To determine the contribution of retinal and non-retinal mechanisms to extraclassical suppression in the feline, we made simultaneous single-unit recordings from synaptically connected retinal ganglion cells and LGN neurons and measured the influence of stimulus size on the spiking activity of pre- and postsynaptic neurons. Results show that extraclassical suppression is significantly stronger for LGN neurons than for their retinal inputs, indicating a role for extra-retinal mechanisms. Further analysis reveals that the enhanced suppression can be accounted for by mechanisms that suppress the effectiveness of retinal inputs in evoking LGN spikes. Finally, an examination of the time course for the onset of extraclassical suppression in the LGN and the size-dependent modulation of retinal spike efficacy suggests the early phase of augmented suppression involves local thalamic circuits. Taken together, these results demonstrate that the LGN is much more than a simple relay for retinal signals to cortex; it dynamically filters retinal spikes on the basis of stimulus statistics to adjust the gain of visual signals delivered to cortex.The lateral geniculate nucleus (LGN) is the gateway through which retinal information reaches the cerebral cortex. Within the LGN, neuronal responses are often suppressed by stimuli that extend beyond the classical receptive field. This form of suppression, called extraclassical suppression serves to adjust the size tuning, response gain, and temporal response properties of neurons. Given the important influence of extraclassical suppression on visual signals delivered to cortex, we performed experiments to determine the circuit mechanisms that contribute to extraclassical suppression in the LGN. Results show that suppression is augmented beyond that provided by direct retinal inputs and delayed, consistent with polysynaptic inhibition. Importantly, these mechanisms influence the effectiveness of incoming retinal signals, thereby filtering the signals ultimately conveyed to cortex.

UnlabelledMyelin controls the time required for an action potential to travel from the neuronal soma to the axon terminal, defining the temporal manner in which information is processed within the CNS. The presence of myelin, the internodal length, and the thickness of the myelin sheath are powerful structural factors that control the velocity and fidelity of action potential transmission. Emerging evidence indicates that myelination is sensitive to environmental experience and neuronal activity. Activity-dependent modulation of myelination can dynamically alter action potential conduction properties but direct functional in vivo evidence and characterization of the underlying myelin changes is lacking. We demonstrate that in mice long-term monocular deprivation increases oligodendrogenesis in the retinogeniculate pathway but shortens myelin internode lengths without affecting other structural properties of myelinated fibers. We also demonstrate that genetically attenuating synaptic glutamate neurotransmission from retinal ganglion cells phenocopies the changes observed after monocular deprivation, suggesting that glutamate may constitute a signal for myelin length regulation. Importantly, we demonstrate that visual deprivation and shortened internodes are associated with a significant reduction in nerve conduction velocity in the optic nerve. Our results reveal the importance of sensory input in the building of myelinated fibers and suggest that this activity-dependent alteration of myelination is important for modifying the conductive properties of brain circuits in response to environmental experience.Significance statementOligodendrocyte precursor cells differentiate into mature oligodendrocytes and are capable of ensheathing axons with myelin without molecular cues from neurons. However, this default myelination process can be modulated by changes in neuronal activity. Here, we show, for the first time, that experience-dependent activity modifies the length of myelin internodes along axons altering action potential conduction velocity. Such a mechanism would allow for variations in conduction velocities that provide a degree of plasticity in accordance to environmental needs. It will be important in future work to investigate how these changes in myelination and conduction velocity contribute to signal integration in postsynaptic neurons and circuit function.

Corticothalamic circuits are essential for reciprocal information exchange between the thalamus and cerebral cortex. Nevertheless, the role of corticothalamic circuits in sensory processing remains a mystery. In the visual system, afferents from retina to the lateral geniculate nucleus (LGN) and from LGN to primary visual cortex (V1) are organized into functionally distinct parallel processing streams. Physiological evidence suggests corticogeniculate feedback may be organized into parallel streams; however, little is known about the diversity of corticogeniculate neurons, their local computations, or the structure-function relationship among corticogeniculate neurons. We used a virus-mediated approach to label and reconstruct the complete dendritic and local axonal arbors of identified corticogeniculate neurons in the macaque monkey. Our results reveal morphological substrates for parallel streams of corticogeniculate feedback based on distinct classes of neurons in V1 and V2. These results support the hypothesis that distinct populations of feedback neurons provide independent and unique information to the LGN.

Biological sensory systems share a number of organizing principles. One such principle is the formation of parallel streams. In the visual system, information about bright and dark features is largely conveyed via two separate streams: theONandOFFpathways. While brightness and darkness can be considered symmetric and opposite forms of visual contrast, the response properties of cells in theONandOFFpathways are decidedly asymmetric. Here, we ask whether a simple contrast-encoding model predicts asymmetries for brights and darks that are similar to the asymmetries found in theONandOFFpathways. Importantly, this model does not include any explicit differences in how the visual system represents brights and darks, but it does include a common normalization mechanism. The phenomena captured by the model include (1) nonlinear contrast response functions, (2) greater nonlinearities in the responses to darks, and (3) larger responses to dark contrasts. We report a direct, quantitative comparison between these model predictions and previously published electrophysiological measurements from the retina and thalamus (guinea pig and cat, respectively). This work suggests that the simple computation of visual contrast may account for a range of early visual processing nonlinearities. Assessing explicit models of sensory representations is essential for understanding which features of neuronal activity these models can and cannot predict, and for investigating how early computations may reverberate through the sensory pathways.

Neuronal signals conveying luminance contrast play a key role in nearly all aspects of perception, including depth perception, texture discrimination, and motion perception. Although much is known about the retinal mechanisms responsible for encoding contrast information, relatively little is known about the relationship between stimulus contrast and the processing of neuronal signals between visual structures. Here, we describe simultaneous recordings from monosynaptically connected retinal ganglion cells and lateral geniculate nucleus (LGN) neurons in the cat to determine how stimulus contrast affects the communication of visual signals between the two structures. Our results indicate that: (1) LGN neurons typically reach their half-maximal response at lower contrasts than their individual retinal inputs and (2) LGN neurons exhibit greater contrast-dependent phase advance (CDPA) than their retinal inputs. Further analyses suggests that increased sensitivity relies on spatial convergence of multiple retinal inputs, while increased CDPA is achieved, in part, on temporal summation of arriving signals.

Stream segregation enables a listener to disentangle multiple competing sequences of sounds. A recent study from our laboratory demonstrated that cortical neurons in anesthetized cats exhibit spatial stream segregation (SSS) by synchronizing preferentially to one of two sequences of noise bursts that alternate between two source locations. Here, we examine the emergence of SSS along the ascending auditory pathway. Extracellular recordings were made in anesthetized rats from the inferior colliculus (IC), the nucleus of the brachium of the IC (BIN), the medial geniculate body (MGB), and the primary auditory cortex (A1). Stimuli consisted of interleaved sequences of broadband noise bursts that alternated between two source locations. At stimulus presentation rates of 5 and 10 bursts per second, at which human listeners report robust SSS, neural SSS is weak in the central nucleus of the IC (ICC), it appears in the nucleus of the brachium of the IC (BIN) and in approximately two-thirds of neurons in the ventral MGB (MGBv), and is prominent throughout A1. The enhancement of SSS at the cortical level reflects both increased spatial sensitivity and increased forward suppression. We demonstrate that forward suppression in A1 does not result from synaptic inhibition at the cortical level. Instead, forward suppression might reflect synaptic depression in the thalamocortical projection. Together, our findings indicate that auditory streams are increasingly segregated along the ascending auditory pathway as distinct mutually synchronized neural populations.Significance statementListeners are capable of disentangling multiple competing sequences of sounds that originate from distinct sources. This stream segregation is aided by differences in spatial location between the sources. A possible substrate of spatial stream segregation (SSS) has been described in the auditory cortex, but the mechanisms leading to those cortical responses are unknown. Here, we investigated SSS in three levels of the ascending auditory pathway with extracellular unit recordings in anesthetized rats. We found that neural SSS emerges within the ascending auditory pathway as a consequence of sharpening of spatial sensitivity and increasing forward suppression. Our results highlight brainstem mechanisms that culminate in SSS at the level of the auditory cortex.

Visually evoked activity is necessary for the normal development of the visual system. However, little is known about the capacity for patterned spontaneous activity to drive the maturation of receptive fields before visual experience. Retinal waves provide instructive retinotopic information for the anatomical organization of the visual thalamus. To determine whether retinal waves also drive the maturation of functional responses, we increased the frequency of retinal waves pharmacologically in the ferret (Mustela putorius furo) during a period of retinogeniculate development before eye opening. The development of geniculate receptive fields after receiving these increased neural activities was measured using single-unit electrophysiology. We found that increased retinal waves accelerate the developmental reduction of geniculate receptive field sizes. This reduction is due to a decrease in receptive field center size rather than an increase in inhibitory surround strength. This work reveals an instructive role for patterned spontaneous activity in guiding the functional development of neural circuits.

Current models of retinogeniculate development have proposed that connectivity between the retina and the dorsal lateral geniculate nucleus (dLGN) is established by gradients of axon guidance molecules, to allow initial coarse connections, and by competitive Hebbian-like processes, to drive eye-specific segregation and refine retinotopy. Here we show that when intereye competition is eliminated by monocular enucleation, blocking cholinergic stage II retinal waves disrupts the intraeye competition-mediated expansion of the retinogeniculate projection and results in the permanent disorganization of its laminae. This disruption of stage II retinal waves also causes long-term impacts on receptive field size and fine-scale retinotopy in the dLGN. Our results reveal a novel role for stage II retinal waves in regulating retinogeniculate afferent terminal targeting by way of intraeye competition, allowing for correct laminar patterning and the even allocation of synaptic territory. These findings should contribute to answering questions regarding the role of neural activity in guiding the establishment of neural circuits.

Locations of sounds are computed in the central auditory pathway based primarily on differences in sound level and timing at the two ears. In rats, the results of that computation appear in the primary auditory cortex (A1) as exclusively contralateral hemifield spatial sensitivity, with strong responses to sounds contralateral to the recording site, sharp cutoffs across the midline, and weak, sound-level-tolerant responses to ipsilateral sounds. We surveyed the auditory pathway in anesthetized rats to identify the brain level(s) at which level-tolerant spatial sensitivity arises. Noise-burst stimuli were varied in horizontal sound location and in sound level. Neurons in the central nucleus of the inferior colliculus (ICc) displayed contralateral tuning at low sound levels, but tuning was degraded at successively higher sound levels. In contrast, neurons in the nucleus of the brachium of the inferior colliculus (BIN) showed sharp, level-tolerant spatial sensitivity. The ventral division of the medial geniculate body (MGBv) contained two discrete neural populations, one showing broad sensitivity like the ICc and one showing sharp sensitivity like A1. Dorsal, medial, and shell regions of the MGB showed fairly sharp spatial sensitivity, likely reflecting inputs from A1 and/or the BIN. The results demonstrate two parallel brainstem pathways for spatial hearing. The tectal pathway, in which sharp, level-tolerant spatial sensitivity arises between ICc and BIN, projects to the superior colliculus and could support reflexive orientation to sounds. The lemniscal pathway, in which such sensitivity arises between ICc and the MGBv, projects to the forebrain to support perception of sound location.

Extraclassical surround suppression strongly modulates responses of neurons in the retina, lateral geniculate nucleus (LGN), and primary visual cortex. Although a great deal is known about the spatial properties of extraclassical suppression and the role it serves in stimulus size tuning, relatively little is known about how extraclassical suppression shapes visual processing in the temporal domain. We recorded the spiking activity of retinal ganglion cells and LGN neurons in the cat to test the hypothesis that extraclassical suppression influences temporal features of visual responses in the early visual system. Our results demonstrate that extraclassical suppression not only shifts the distribution of interspike intervals in a manner that decreases the efficacy of neuronal communication, it also decreases the reliability of neuronal responses to visual stimuli and it decreases the duration of visual responses, an effect that underlies a rightward shift in the temporal frequency tuning of LGN neurons. Taken together, these results reveal a dynamic relationship between extraclassical suppression and the temporal features of neuronal responses.

Early in development, before the onset of vision, the retina establishes direction-selective responses. During this time period, the retina spontaneously generates bursts of action potentials that propagate across its extent. The precise spatial and temporal properties of these "retinal waves" have been implicated in the formation of retinal projections to the brain. However, their role in the development of direction selective circuits within the retina has not yet been determined. We addressed this issue by combining multielectrode array and cell-attached recordings to examine mice that lack the CaV3.2 subunit of T-type Ca2+ channels (CaV3.2 KO) because these mice exhibit disrupted waves during the period that direction selective circuits are established. We found that the spontaneous activity of these mice displays wave-associated bursts of action potentials that are altered from that of control mice: the frequency of these bursts is significantly decreased and the firing rate within each burst is reduced. Moreover, the projection patterns of the retina demonstrate decreased eye-specific segregation in the dorsal lateral geniculate nucleus (dLGN). However, after eye-opening, the direction selective responses of CaV3.2 KO direction selective ganglion cells (DSGCs) are indistinguishable from those of wild-type DSGCs. Our data indicate that although the temporal properties of the action potential bursts associated with retinal waves are important for activity-dependent refining of retinal projections to central targets, they are not critical for establishing direction selectivity in the retina.

The segregation and maintenance of eye-specific inputs in the dorsal lateral geniculate nucleus (dLGN) during early postnatal development requires the patterned spontaneous activity of retinal waves. In contrast to the development of the mouse, ferret eye-specific segregation is not complete at the start of stage III glutamatergic retinal waves, and the remaining overlap is limited to the C/C1 lamina of the dLGN. To investigate the role of patterned spontaneous activity in this late segregation, we disrupted retinal waves pharmacologically for 5 day windows from postnatal day (P) 10 to P25. Multi-electrode array recordings of the retina in vitro reveal that the cholinergic agonist epibatidine disrupts correlated retinal activity during stage III waves. Epibatidine also prevents the segregation of eye-specific inputs in vivo during that period. Our results reveal a novel role for cholinergic influence on stage III retinal waves as an instructive signal for the continued segregation of eye-specific inputs in the ferret dLGN.

BackgroundSpontaneous retinal activity (SRA) is important during eye-specific segregation within the dorsal lateral geniculate nucleus (dLGN), but the feature(s) of activity critical for retinogeniculate refinement are controversial. Pharmacologically or genetically manipulating cholinergic signaling during SRA perturbs correlated retinal ganglion cell (RGC) spiking and disrupts eye-specific retinofugal refinement in vivo, consistent with an instructive role for SRA during visual system development. Paradoxically, ablating the starburst amacrine cells (SACs) that generate cholinergic spontaneous activity disrupts correlated RGC firing without impacting retinal activity levels or eye-specific segregation in the dLGN. Such experiments suggest that patterned SRA during retinal waves is not critical for eye-specific refinement and instead, normal activity levels are permissive for retinogeniculate development. Here we revisit the effects of ablating the cholinergic network during eye-specific segregation and show that SAC ablation disrupts, but does not eliminate, retinal waves with no concomitant impact on normal eye-specific segregation in the dLGN.ResultsWe induced SAC ablation in postnatal ferret pups beginning at birth by intraocular injection of a novel immunotoxin selective for the ferret vesicular acetylcholine transporter (Ferret VAChT-Sap). Through dual-patch whole-cell and multi-electrode array recording we found that SAC ablation altered SRA patterns and led to significantly smaller retinal waves compared with controls. Despite these defects, eye-specific segregation was normal. Further, interocular competition for target territory in the dLGN proceeded in cases where SAC ablation was asymmetric in the two eyes.ConclusionsOur data demonstrate normal eye-specific retinogeniculate development despite significant abnormalities in patterned SRA. Comparing our current results with earlier studies suggests that defects in retinal wave size, absolute levels of SRA, correlations between RGC pairs, RGC burst frequency, high frequency RGC firing during bursts, and the number of spikes per RGC burst are each uncorrelated with abnormalities in eye-specific segregation in the dLGN. An increase in the fraction of asynchronous spikes occurring outside of bursts and waves correlates with eye-specific segregation defects in studies reported to date. These findings highlight the relative importance of different features of SRA while providing additional constraints for computational models of Hebbian plasticity mechanisms in the developing visual system.

The magnocellular (M) and parvocellular (P) subdivisions of primate LGN are known to process complementary types of visual stimulus information, but a method for noninvasively defining these subdivisions in humans has proven elusive. As a result, the functional roles of these subdivisions in humans have not been investigated physiologically. To functionally map the M and P subdivisions of human LGN, we used high-resolution fMRI at high field (7 T and 3 T) together with a combination of spatial, temporal, luminance, and chromatic stimulus manipulations. We found that stimulus factors that differentially drive magnocellular and parvocellular neurons in primate LGN also elicit differential BOLD fMRI responses in human LGN and that these responses exhibit a spatial organization consistent with the known anatomical organization of the M and P subdivisions. In test-retest studies, the relative responses of individual voxels to M-type and P-type stimuli were reliable across scanning sessions on separate days and across sessions at different field strengths. The ability to functionally identify magnocellular and parvocellular regions of human LGN with fMRI opens possibilities for investigating the functions of these subdivisions in human visual perception, in patient populations with suspected abnormalities in one of these subdivisions, and in visual cortical processing streams arising from parallel thalamocortical pathways.

Oscillatory synchronization of neuronal activity has been proposed as a mechanism to modulate effective connectivity between interacting neuronal populations. In the visual system, oscillations in the gamma-frequency range (30-100 Hz) are thought to subserve corticocortical communication. To test whether a similar mechanism might influence subcortical-cortical communication, we recorded local field potential activity from retinotopically aligned regions in the lateral geniculate nucleus (LGN) and primary visual cortex (V1) of alert macaque monkeys viewing stimuli known to produce strong cortical gamma-band oscillations. As predicted, we found robust gamma-band power in V1. In contrast, visual stimulation did not evoke gamma-band activity in the LGN. Interestingly, an analysis of oscillatory phase synchronization of LGN and V1 activity identified synchronization in the alpha (8-14 Hz) and beta (15-30 Hz) frequency bands. Further analysis of directed connectivity revealed that alpha-band interactions mediated corticogeniculate feedback processing, whereas beta-band interactions mediated geniculocortical feedforward processing. These results demonstrate that although the LGN and V1 display functional interactions in the lower frequency bands, gamma-band activity in the alert monkey is largely an emergent property of cortex.

The formation of precise connections between retina and lateral geniculate nucleus (LGN) involves the activity-dependent elimination of some synapses, with strengthening and retention of others. Here we show that the major histocompatibility complex (MHC) class I molecule H2-D(b) is necessary and sufficient for synapse elimination in the retinogeniculate system. In mice lacking both H2-K(b) and H2-D(b) (K(b)D(b)(-/-)), despite intact retinal activity and basal synaptic transmission, the developmentally regulated decrease in functional convergence of retinal ganglion cell synaptic inputs to LGN neurons fails and eye-specific layers do not form. Neuronal expression of just H2-D(b) in K(b)D(b)(-/-) mice rescues both synapse elimination and eye-specific segregation despite a compromised immune system. When patterns of stimulation mimicking endogenous retinal waves are used to probe synaptic learning rules at retinogeniculate synapses, long-term potentiation (LTP) is intact but long-term depression (LTD) is impaired in K(b)D(b)(-/-) mice. This change is due to an increase in Ca(2+)-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Restoring H2-D(b) to K(b)D(b)(-/-) neurons renders AMPA receptors Ca(2+) impermeable and rescues LTD. These observations reveal an MHC-class-I-mediated link between developmental synapse pruning and balanced synaptic learning rules enabling both LTD and LTP, and demonstrate a direct requirement for H2-D(b) in functional and structural synapse pruning in CNS neurons.

Normal cerebral cortical function requires a highly ordered balance between projection neurons and interneurons. During development these two neuronal populations migrate from distinct progenitor zones to form the cerebral cortex, with interneurons originating in the more distant ganglionic eminences. Moreover, deficits in interneurons have been linked to a variety of neurodevelopmental disorders underscoring the importance of understanding interneuron development and function. We, and others, have identified SDF1 signaling as one important modulator of interneuron migration speed and leading process branching behavior in mice, although how SDF1 signaling impacts these behaviors remains unknown. We previously found SDF1 inhibited leading process branching while increasing the rate of migration. We have now mechanistically linked SDF1 modulation of leading process branching behavior to a dual regulation of both actin and microtubule organization. We find SDF1 consolidates actin at the leading process tip by de-repressing calpain protease and increasing proteolysis of branched-actin-supporting cortactin. Additionally, SDF1 stabilizes the microtubule array in the leading process through activation of the microtubule-associated protein doublecortin (DCX). DCX stabilizes the microtubule array by bundling microtubules within the leading process, reducing branching. These data provide mechanistic insight into the regulation of interneuron leading process dynamics during neuronal migration in mice and provides insight into how cortactin and DCX, a known human neuronal migration disorder gene, participate in this process.

Cochlear implant electrical stimulation of the auditory system to rehabilitate deafness has been remarkably successful. Its deployment requires both an intact auditory nerve and a suitably patent cochlear lumen. When disease renders prerequisite conditions impassable, such as in neurofibromatosis type II and cochlear obliterans, alternative treatment targets are considered. Electrical stimulation of the cochlear nucleus and midbrain in humans has delivered encouraging clinical outcomes, buttressing the promise of central auditory prostheses to mitigate deafness in those who are not candidates for cochlear implantation. In this study we explored another possible implant target: the auditory thalamus. In anesthetized cats, we first presented pure tones to determine frequency preferences of thalamic and cortical sites. We then electrically stimulated tonotopically organized thalamic sites while recording from primary auditory cortical sites using a multichannel recording probe. Cathode-leading biphasic thalamic stimulation thresholds that evoked cortical responses were much lower than published accounts of cochlear and midbrain stimulation. Cortical activation dynamic ranges were similar to those reported for cochlear stimulation, but they were narrower than those found through midbrain stimulation. Our results imply that thalamic stimulation can activate auditory cortex at low electrical current levels and suggest an auditory thalamic implant may be a viable central auditory prosthesis.

BackgroundThere are numerous functional types of retinal ganglion cells (RGCs), each participating in circuits that encode a specific aspect of the visual scene. This functional specificity is derived from distinct RGC morphologies and selective synapse formation with other retinal cell types; yet, how these properties are established during development remains unclear. Islet2 (Isl2) is a LIM-homeodomain transcription factor expressed in the developing retina, including approximately 40% of all RGCs, and has previously been implicated in the subtype specification of spinal motor neurons. Based on this, we hypothesized that Isl2+ RGCs represent a related subset that share a common function.ResultsWe morphologically and molecularly characterized Isl2+ RGCs using a transgenic mouse line that expresses GFP in the cell bodies, dendrites and axons of Isl2+ cells (Isl2-GFP). Isl2-GFP RGCs have distinct morphologies and dendritic stratification patterns within the inner plexiform layer and project to selective visual nuclei. Targeted filling of individual cells reveals that the majority of Isl2-GFP RGCs have dendrites that are monostratified in layer S3 of the IPL, suggesting they are not ON-OFF direction-selective ganglion cells. Molecular analysis shows that most alpha-RGCs, indicated by expression of SMI-32, are also Isl2-GFP RGCs. Isl2-GFP RGCs project to most retino-recipient nuclei during early development, but specifically innervate the dorsal lateral geniculate nucleus and superior colliculus (SC) at eye opening. Finally, we show that the segregation of Isl2+ and Isl2- RGC axons in the SC leads to the segregation of functional RGC types.ConclusionsTaken together, these data suggest that Isl2+ RGCs comprise a distinct class and support a role for Isl2 as an important component of a transcription factor code specifying functional visual circuits. Furthermore, this study describes a novel genetically-labeled mouse line that will be a valuable resource in future investigations of the molecular mechanisms of visual circuit formation.

The spatial components of a visual scene are processed neurally in a sequence of coarse features followed by fine features. This coarse-to-fine temporal stream was initially considered to be a cortical function, but has recently been demonstrated in the dorsal lateral geniculate nucleus. The goal of this study was to test the hypothesis that coarse-to-fine processing is present at earlier stages of visual processing in the retinal ganglion cells that supply lateral geniculate nucleus (LGN) neurons. To compare coarse-to-fine processing in the cat's visual system, we measured the visual responses of connected neuronal pairs from the retina and LGN, and separate populations of cells from each region. We found that coarse-to-fine processing was clearly present at the ganglion cell layer of the retina. Interestingly, peak and high-spatial-frequency cutoff responses were higher in the LGN than in the retina, indicating that there was a progressive cascade of coarse-to-fine information from the retina to the LGN to the visual cortex. The analysis of early visual pathway receptive field characteristics showed that the physiological response interplay between the center and surround regions was consistent with coarse-to-fine features and may provide a primary role in the underlying mechanism. Taken together, the results from this study provided a framework for understanding the emergence and refinement of coarse-to-fine processing in the visual system.

Fast sensory processing is vital for the animal to efficiently respond to the changing environment. This is usually achieved when the animal is vigilant, as reflected by cortical desynchronization. However, the neural substrate for such fast processing remains unclear. Here, we report that neurons in rat primary visual cortex (V1) exhibited shorter response latency in the desynchronized state than in the synchronized state. In vivo whole-cell recording from the same V1 neurons undergoing the two states showed that both the resting and visually evoked conductances were higher in the desynchronized state. Such conductance increases of single V1 neurons shorten the response latency by elevating the membrane potential closer to the firing threshold and reducing the membrane time constant, but the effects only account for a small fraction of the observed latency advance. Simultaneous recordings in lateral geniculate nucleus (LGN) and V1 revealed that LGN neurons also exhibited latency advance, with a degree smaller than that of V1 neurons. Furthermore, latency advance in V1 increased across successive cortical layers. Thus, latency advance accumulates along various stages of the visual pathway, likely due to a global increase of membrane conductance in the desynchronized state. This cumulative effect may lead to a dramatic shortening of response latency for neurons in higher visual cortex and play a critical role in fast processing for vigilant animals.

Parallel visual pathways from the retina to the primary visual cortex (V1) via the lateral geniculate nucleus are common to many mammalian species, including mice, carnivores, and primates. However, it remains unclear which visual features present in both retina and V1 may be inherited from parallel pathways versus extracted by V1 circuits in the mouse. Here, using calcium imaging and rabies circuit tracing, we explore the relationships between tuning of layer 4 (L4) V1 neurons and their retinal ganglion cell (RGC) inputs. We find that subpopulations of L4 V1 neurons differ in their tuning for direction, orientation, spatial frequency, temporal frequency, and speed. Furthermore, we find that direction-tuned L4 V1 neurons receive input from direction-selective RGCs, whereas orientation-tuned L4 V1 neurons receive input from orientation-selective RGCs. These results suggest that direction and orientation tuning of V1 neurons may be partly inherited from parallel pathways originating in the retina., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In prairie voles, primary sensory areas are dominated by neurons that respond to one sensory modality, but some neurons also respond to stimulation of other modalities. To reveal the anatomical substrate for these multimodal responses, we examined the connections of the primary auditory area + the anterior auditory field (A1 + AAF), the temporal anterior area (TA), and the primary visual area (V1). A1 + AAF had intrinsic connections and connections with TA, multimodal cortex (MM), V1, and primary somatosensory area (S1). TA had intrinsic connections and connections with A1 + AAF, MM, and V2. Callosal connections were observed in homotopic locations in auditory cortex for both fields. A1 + AAF and TA receive thalamic input primarily from divisions of the medial geniculate nucleus but also from the lateral geniculate nucleus (LGd), the lateral posterior nucleus, and the ventral posterior nucleus (VP). V1 had dense intrinsic connections and connections with V2, MM, auditory cortex, pyriform cortex (Pyr), and, in some cases, somatosensory cortex. V1 had interhemispheric connections with V1, V2, MM, S1, and Pyr and received thalamic input from LGd and VP. Our results indicate that multisensory integration occurs in primary sensory areas of the prairie vole cortex, and this may be related to behavioral specializations associated with its niche.

With the current techniques available for mapping receptive fields, it is impossible to resolve the contribution of single cone photoreceptors to the response of central visual neurons. Using adaptive optics to correct for ocular aberrations, we delivered micron-scale spots of light to the receptive field centers of neurons in the macaque lateral geniculate nucleus. Parvocellular LGN neurons mapped in this manner responded with high reliability to stimulation of single cones.

In all mammalian species the projections of the two eyes to the dorsal lateral geniculate nucleus are initially overlapping before gradually forming the eye-specific domains evident at maturity. It is widely thought that retinal waves of neuronal activity play an instructional role in this developmental process. Here, I discuss the myriad reasons why retinal waves are unlikely to have such a role, and suggest that eye-specific molecular cues in combination with neuronal activity are most probably involved in the formation of eye-specific retinogeniculate projections.

Prior to eye-opening and the development of visual responses, the retina exhibits highly correlated spontaneous firing pattens termed retinal waves. Disruption of the normal spontaneous firing pattern either genetically or pharmacologically prevents the eye-specific refinement of retinogeniculate afferents. Here I provide the evidence that retinal waves play an instructive role in this process. In addition, I argue that a full understanding requires an identification of the features of retinal activity that drive the refinement as well as an understanding of mechanisms that transform these signals into axonal rearrangements.

The basic structure of receptive fields and functional maps in primary visual cortex is established without exposure to normal sensory experience and before the onset of the critical period. How the brain wires these circuits in the early stages of development remains unknown. Possible explanations include activity-dependent mechanisms driven by spontaneous activity in the retina and thalamus, and molecular guidance orchestrating thalamo-cortical connections on a fine spatial scale. Here I propose an alternative hypothesis: the blueprint for receptive fields, feature maps, and their inter-relationships may reside in the layout of the retinal ganglion cell mosaics along with a simple statistical connectivity scheme dictating the wiring between thalamus and cortex. The model is shown to account for a number of experimental findings, including the relationship between retinotopy, orientation maps, spatial frequency maps and cytochrome oxidase patches. The theory's simplicity, explanatory and predictive power makes it a serious candidate for the origin of the functional architecture of primary visual cortex.

Little is known about the impairments and pathological changes in the visual system in mild brain trauma, especially repetitive mild traumatic brain injury (mTBI). The goal of this study was to examine and compare the effects of repeated head impacts on the neurodegeneration, axonal integrity, and glial activity in the optic tract (OT), as well as on neuronal preservation, glial responses, and synaptic organization in the lateral geniculate nucleus (LGN) and superior colliculus (SC), in wild-type mice and transgenic animals with overexpression of human TDP-43 mutant protein (TDP-43G348C) at 6 months after repeated closed head traumas. Animals were also assessed in the Barnes maze (BM) task. Neurodegeneration, axonal injury, and gliosis were detected in the OT of the injured animals of both genotypes. In the traumatized mice, myelination of surviving axons was mostly preserved, and the expression of neurofilament light chain was unaffected. Repetitive mTBI did not induce changes in the LGN and the SC, nor did it affect the performance of the BM task in the traumatized wild-type and TDP-43 transgenic mice. Differences in neuropathological and behavioral assessments between the injured wild-type and TDP-43G348C mice were not revealed. Results of the current study suggest that repetitive mTBI was associated with chronic damage and inflammation in the OT in wild-type and TDP-43G348C mice, which were not accompanied with behavioral problems and were not affected by the TDP-43 genotype, while the LGN and the SC remained preserved in the used experimental conditions.