A Fine-Scale Functional Logic to Convergence from Retina to Thalamus.

Numerous well-defined classes of retinal ganglion cells innervate the thalamus to guide image-forming vision, yet the rules governing their convergence and divergence remain unknown. Using two-photon calcium imaging in awake mouse thalamus, we observed a functional arrangement of retinal ganglion cell axonal boutons in which coarse-scale retinotopic ordering gives way to fine-scale organization based on shared preferences for other visual features. Specifically, at the ∼6 µm scale, clusters of boutons from different axons often showed similar preferences for either one or multiple features, including axis and direction of motion, spatial frequency, and changes in luminance. Conversely, individual axons could "de-multiplex" information channels by participating in multiple, functionally distinct bouton clusters. Finally, ultrastructural analyses demonstrated that retinal axonal boutons in a local cluster often target the same dendritic domain. These data suggest that functionally specific convergence and divergence of retinal axons may impart diverse, robust, and often novel feature selectivity to visual thalamus.

Dysfunction of the magnocellular subdivision of the visual thalamus in developmental dyslexia.

Developmental dyslexia (DD) is one of the most common learning disorders, affecting millions of children and adults worldwide. To date, scientific research has attempted to explain DD primarily based on pathophysiological alterations in the cerebral cortex. In contrast, several decades ago, pioneering research on five post-mortem human brains suggested that a core characteristic of DD might be morphological alterations in a specific subdivision of the visual thalamus - the magnocellular LGN (M-LGN). However, due to considerable technical challenges in investigating LGN subdivisions non-invasively in humans, this finding was never confirmed in-vivo, and its relevance for DD pathology remained highly controversial. Here, we leveraged recent advances in high-resolution magnetic resonance imaging (MRI) at high field strength (7 Tesla) to investigate the M-LGN in DD in-vivo. Using a case-control design, we acquired data from a large sample of young adults with DD (n = 26; age 28 ± 7 years; 13 females) and matched control participants (n = 28; age 27 ± 6 years; 15 females). Each participant completed a comprehensive diagnostic behavioral test battery and participated in two MRI sessions, including three functional MRI experiments and one structural MRI acquisition. We measured blood-oxygen-level-dependent responses and longitudinal relaxation rates to compare both groups on LGN subdivision function and myelination. Based on previous research, we hypothesized that the M-LGN is altered in DD and that these alterations are associated with a key DD diagnostic score, i.e., rapid letter and number naming (RANln). The results showed aberrant responses of the M-LGN in DD compared to controls, which was reflected in a different functional lateralization of this subdivision between groups. These alterations were associated with RANln performance, specifically in male DD. We also found lateralization differences in the longitudinal relaxation rates of the M-LGN in DD relative to controls. Conversely, the other main subdivision of the LGN, the parvocellular LGN (P-LGN), showed comparable blood-oxygen-level-dependent responses and longitudinal relaxation rates between groups. The present study is the first to unequivocally show that M-LGN alterations are a hallmark of DD, affecting both the function and microstructure of this subdivision. It further provides a first functional interpretation of M-LGN alterations and a basis for a better understanding of sex-specific differences in DD with implications for prospective diagnostic and treatment strategies.

Effects of Mild Closed-Head Injury and Subanesthetic Ketamine Infusion on Microglia, Axonal Injury, and Synaptic Density in Sprague-Dawley Rats.

Mild traumatic brain injury (mTBI) affects millions of people in the U.S. Approximately 20-30% of those individuals develop adverse symptoms lasting at least 3 months. In a rat mTBI study, the closed-head impact model of engineered rotational acceleration (CHIMERA) produced significant axonal injury in the optic tract (OT), indicating white-matter damage. Because retinal ganglion cells project to the lateral geniculate nucleus (LGN) in the thalamus through the OT, we hypothesized that synaptic density may be reduced in the LGN of rats following CHIMERA injury. A modified SEQUIN (synaptic evaluation and quantification by imaging nanostructure) method, combined with immunofluorescent double-labeling of pre-synaptic (synapsin) and post-synaptic (PSD-95) markers, was used to quantify synaptic density in the LGN. Microglial activation at the CHIMERA injury site was determined using Iba-1 immunohistochemistry. Additionally, the effects of ketamine, a potential neuroprotective drug, were evaluated in CHIMERA-induced mTBI. A single-session repetitive (ssr-) CHIMERA (3 impacts, 1.5 joule/impact) produced mild effects on microglial activation at the injury site, which was significantly enhanced by post-injury intravenous ketamine (10 mg/kg) infusion. However, ssr-CHIMERA did not alter synaptic density in the LGN, although ketamine produced a trend of reduction in synaptic density at post-injury day 4. Further research is necessary to characterize the effects of ssr-CHIMERA and subanesthetic doses of intravenous ketamine on different brain regions and multiple time points post-injury. The current study demonstrates the utility of the ssr-CHIMERA as a rodent model of mTBI, which researchers can use to identify biological mechanisms of mTBI and to develop improved treatment strategies for individuals suffering from head trauma.

Inner Structure of the Lateral Geniculate Complex of Adult and Newborn Acomys cahirinus.

Acomys cahirinus is a unique Rodentia species with several distinctive physiological traits, such as precocial development and remarkable regenerative abilities. These characteristics render A. cahirinus increasingly valuable for regenerative and developmental physiology studies. Despite this, the structure and postnatal development of the central nervous system in A. cahirinus have been inadequately explored, with only sporadic data available. This study is the first in a series of papers addressing these gaps. Our first objective was to characterize the structure of the main visual thalamic region, the lateral geniculate complex, using several neuronal markers (including Ca2+-binding proteins, glutamic acid decarboxylase enzyme, and non-phosphorylated domains of heavy-chain neurofilaments) to label populations of principal neurons and interneurons in adult and newborn A. cahirinus. As typically found in other rodents, we identified three subdivisions in the geniculate complex: the dorsal and ventral lateral geniculate nuclei (LGNd and LGNv) and the intergeniculate leaflet (IGL). Additionally, we characterized internal diversity in the LGN nuclei. The "shell" and "core" regions of the LGNd were identified using calretinin in adults and newborns. In adults, the inner and outer parts of the LGNv were identified using calbindin, calretinin, parvalbumin, GAD67, and SMI-32, whereas in newborns, calretinin and SMI-32 were employed for this purpose. Our findings revealed more pronounced developmental changes in LGNd compared to LGNv and IGL, suggesting that LGNd is less mature at birth and more influenced by visual experience.

Metabolic cues impact non-oscillatory intergeniculate leaflet and ventral lateral geniculate nucleus: standard versus high-fat diet comparative study.

The intergeniculate leaflet and ventral lateral geniculate nucleus (IGL/VLG) are subcortical structures involved in entrainment of the brain's circadian system to photic and non-photic (e.g. metabolic and arousal) cues. Both receive information about environmental light from photoreceptors, exhibit infra-slow oscillations (ISO) in vivo, and connect to the master circadian clock. Although current evidence demonstrates that the IGL/VLG communicate metabolic information and are crucial for entrainment of circadian rhythms to time-restricted feeding, their sensitivity to food intake-related peptides has not been investigated yet. We examined the effect of metabolically relevant peptides on the spontaneous activity of IGL/VLG neurons. Using ex vivo and in vivo electrophysiological recordings as well as in situ hybridisation, we tested potential sensitivity of the IGL/VLG to anorexigenic and orexigenic peptides, such as cholecystokinin, glucagon-like peptide 1, oxyntomodulin, peptide YY, orexin A and ghrelin. We explored neuronal responses to these drugs during day and night, and in standard vs. high-fat diet conditions. We found that IGL/VLG neurons responded to all the substances tested, except peptide YY. Moreover, more neurons responded to anorexigenic drugs at night, while a high-fat diet affected the IGL/VLG sensitivity to orexigenic peptides. Interestingly, ISO neurons responded to light and orexin A, but did not respond to the other food intake-related peptides. In contrast, non-ISO cells were activated by metabolic peptides, with only some being responsive to light. Our results show for the first time that peptides involved in the body's energy homeostasis stimulate the thalamus and suggest functional separation of the IGL/VLG cells. KEY POINTS: The intergeniculate leaflet and ventral lateral geniculate nucleus (IGL/VLG) of the rodent thalamus process various signals and participate in circadian entrainment. In both structures, cells exhibiting infra-slow oscillatory activity as well as non-rhythmically firing neurons being observed. Here, we reveal that only one of these two groups of cells responds to anorexigenic (cholecystokinin, glucagon-like peptide 1 and oxyntomodulin) and orexigenic (ghrelin and orexin A) peptides. Neuronal responses vary depending on the time of day (day vs. night) and on the diet (standard vs. high-fat diet). Additionally, we visualised receptors to the tested peptides in the IGL/VLG using in situ hybridisation. Our results suggest that two electrophysiologically different subpopulations of IGL/VLG neurons are involved in two separate functions: one related to the body's energy homeostasis and one associated with the subcortical visual system.

Macromolecular tissue volume mapping of lateral geniculate nucleus subdivisions in living human brains.

The lateral geniculate nucleus (LGN) is a key thalamic nucleus in the visual system, which has an important function in relaying retinal visual input to the visual cortex. The human LGN is composed mainly of magnocellular (M) and parvocellular (P) subdivisions, each of which has different stimulus selectivity in neural response properties. Previous studies have discussed the potential relationship between LGN subdivisions and visual disorders based on psychophysical data on specific types of visual stimuli. However, these relationships remain speculative because non-invasive measurements of these subdivisions are difficult due to the small size of the LGN. Here we propose a method to identify these subdivisions by combining two structural MR measures: high-resolution proton-density weighted images and macromolecular tissue volume (MTV) maps. We defined the M and P subdivisions based on MTV fraction data and tested the validity of the definition by (1) comparing the data with that from human histological studies, (2) comparing the data with functional magnetic resonance imaging measurements on stimulus selectivity, and (3) analyzing the test-retest reliability. The findings demonstrated that the spatial organization of the M and P subdivisions was consistent across subjects and in line with LGN subdivisions observed in human histological data. Moreover, the difference in stimulus selectivity between the subdivisions identified using MTV was consistent with previous physiology literature. The definition of the subdivisions based on MTV was shown to be robust over measurements taken on different days. These results suggest that MTV mapping is a promising approach for evaluating the tissue properties of LGN subdivisions in living humans. This method potentially will enable neuroscientific and clinical hypotheses about the human LGN subdivisions to be tested.

Evolution of Local Circuit Neurons in Two Sensory Thalamic Nuclei in Amniotes.

Local circuit neurons are present in the thalamus of all vertebrates where they are considered inhibitory. They play an important role in computation and influence the transmission of information from the thalamus to the telencephalon. In mammals, the percentage of local circuit neurons in the dorsal lateral geniculate nucleus remains relatively constant across a variety of species. In contrast, the numbers of local circuit neurons in the ventral division of the medial geniculate body in mammals vary significantly depending on the species examined. To explain these observations, the numbers of local circuit neurons were investigated by reviewing the literature on this subject in these two nuclei in mammals and their respective homologs in sauropsids and by providing additional data on a crocodilian. Local circuit neurons are present in the dorsal geniculate nucleus of sauropsids just as is the case for this nucleus in mammals. However, sauropsids lack local circuits neurons in the auditory thalamic nuclei homologous to the ventral division of the medial geniculate body. A cladistic analysis of these results suggests that differences in the numbers of local circuit neurons in the dorsal lateral geniculate nucleus of amniotes reflect an elaboration of these local circuit neurons as a result of evolution from a common ancestor. In contrast, the numbers of local circuit neurons in the ventral division of the medial geniculate body changed independently in several mammalian lineages.

Clinical characteristics and risk factors for bilateral lateral geniculate body pathology: a systematic review of the literature.

BACKGROUND: Case presentation of acute onset bilateral painless vision loss caused by bilateral infarction of the lateral geniculate bodies (LGB) and a systematic review of the literature. METHODS: A descriptive case report is presented on a 17-year-old female diagnosed with acute pancreatitis who developed acute onset bilateral painless vision loss. A systematic literature review of cases with bilateral LGB lesions was conducted across three electronic databases (PubMed/PubMed Central/MEDLINE, Scopus, and ScienceDirect). The review was conducted in concordance with PRISMA guidelines and prospectively registered on PROSPERO (CRD42022362491). RESULTS: The reported 17-year-old female was found to have MRI findings consistent with bilateral hemorrhagic infarction of the LGB and Purtscher-like retinopathy. A systematic literature review of bilateral LGB infarction yielded 23 records for analysis. 19/23 (82.6%) of reported cases occurred in women. Bilateral vision loss was noted in all cases. The average reported age was 27 years old with a range from 2-50. Gastrointestinal pathology (e.g., pancreatitis, gastroenteritis) was present in 8/23 (34.7%) of cases. 8/23 (34.7%) cases had neuroimaging or pathological evidence of hemorrhagic transformation of the infarct. Most cases experienced partial recovery of visual loss; only one case (4.7%) had complete visual recovery. 9/23 (39.1%) cases were reported from the United States and 4/23 (17.3%) from India. CONCLUSIONS: Bilateral LGB lesion is a rare cause of vision loss, typically caused by systemic diseases and with female preponderance. Purported pathophysiology relates to increased vulnerability of the LGB to ischemic and metabolic stress.

Contribution of the Pulvinar and Lateral Geniculate Nucleus to the Control of Visually Guided Saccades in Blindsight Monkeys.

After damage to the primary visual cortex (V1), conscious vision is impaired. However, some patients can respond to visual stimuli presented in their lesion-affected visual field using residual visual pathways bypassing V1. This phenomenon is called "blindsight." Many studies have tried to identify the brain regions responsible for blindsight, and the pulvinar and/or lateral geniculate nucleus (LGN) are suggested to play key roles as the thalamic relay of visual signals. However, there are critical problems regarding these preceding studies in that subjects with different sized lesions and periods of time after lesioning were investigated; furthermore, the ability of blindsight was assessed with different measures. In this study, we used double dissociation to clarify the roles of the pulvinar and LGN by pharmacological inactivation of each region and investigated the effects in a simple task with visually guided saccades (VGSs) using monkeys with a unilateral V1 lesion, by which nearly all of the contralesional visual field was affected. Inactivating either the ipsilesional pulvinar or LGN impaired VGS toward a visual stimulus in the affected field. In contrast, inactivation of the contralesional pulvinar had no clear effect, but inactivation of the contralesional LGN impaired VGS to the intact visual field. These results suggest that the pulvinar and LGN play key roles in performing the simple VGS task after V1 lesioning, and that the visuomotor functions of blindsight monkeys were supported by plastic changes in the visual pathway involving the pulvinar, which emerged after V1 lesioning.SIGNIFICANCE STATEMENT Many studies have been devoted to understanding the mechanism of mysterious symptom called "blindsight," in which patients with damage to the primary visual cortex (V1) can respond to visual stimuli despite loss of visual awareness. However, there is still a debate on the thalamic relay of visual signals. In this study, to pin down the issue, we tried double dissociation in the same subjects (hemi-blindsight macaque monkeys) and clarified that the lateral geniculate nucleus (LGN) plays a major role in simple visually guided saccades in the intact state, while both pulvinar and LGN critically contribute after the V1 lesioning, suggesting that plasticity in the visual pathway involving the pulvinar underlies the blindsight.

Role of AMPA receptor desensitization in short term depression - lessons from retinogeniculate synapses.

Repetitive synapse activity induces various forms of short-term plasticity. The role of presynaptic mechanisms such as residual Ca2+ and vesicle depletion in short-term facilitation and short-term depression is well established. On the other hand, the contribution of postsynaptic mechanisms such as receptor desensitization and saturation to short-term plasticity is less well known and often ignored. In this review, I will describe short-term plasticity in retinogeniculate synapses of relay neurons of the dorsal lateral geniculate nucleus (dLGN) to exemplify the synaptic properties that facilitate the contribution of AMPA receptor desensitization to short-term plasticity. These include high vesicle release probability, glutamate spillover and, importantly, slow recovery from desensitization of AMPA receptors. The latter is strongly regulated by the interaction of AMPA receptors with auxiliary proteins such as CKAMP44. Finally, I discuss the relevance of short-term plasticity in retinogeniculate synapses for the processing of visual information by LGN relay neurons.

DNA damage and repair in the visual center in the rhesus monkey model of glaucoma.

To study the DNA damage and repair methods of visual central neurons in a glaucoma model, a rhesus monkey chronic glaucoma model was established by laser induction, and changes in intraocular pressure (IOP), the optic cup fundus, the thickness of the retinal nerve fiber layer and the diameter of the optic nerve were evaluated. After a sufficient period of time, the model was euthanized, and the lateral geniculate body, primary visual cortex (V1 region) and secondary visual cortex (V2 region) were removed. Through immunofluorescence, ELISA and western blotting assays, the expressions of 8-hydroxyguanosine (8-OHG), a biomarker of oxidative stress, and γH2AX, a marker of DNA double-strand breaks, in the neurons of the LGN, V1 and V2 in the glaucoma model were higher than those of the control group (P < 0.05). The expression of key DNA repair proteins Ku80, Mre11, PCNA, DNA ligase IV and APE1 antibodies in the LGN, V1 and V2 of the glaucoma model was higher than that of the control group (P < 0.05), and in the positive TUNEL cells, the levels of cleaved caspase 3, Beclin 1 and LC3B-II/LC3B-I were significantly increased in the LGN of the glaucoma model (P < 0.05), but there was no significant positive expression in the V1 and V2 regions of the glaucoma model compared with the normal control group (P > 0.05). Transmission electron microscopy also showed that apoptotic bodies and autolysosomes (changes in neuronal apoptosis and autophagy activation) appeared in some neurons of the LGN in glaucoma, but there were no significant abnormal changes in the V1 and V2 regions of glaucoma or in any specimens in the normal group. In terms of neuron counting, the number of neurons in the LGN of the glaucoma model was lower than that in the normal control group (P < 0.05), but there was no significant difference in the number of neurons in the V1 and V2 regions between the two groups (P > 0.05). Similarly, the expression of glial cells in the LGN, V1 and V2 of the glaucoma model was higher than that in the control group (P < 0.05). Therefore, the results showed that DNA oxidative damage and various repair processes occurred in neurons of the LGN, V1 and V2 of the glaucoma model, and finally, LGN neurons died in the glaucoma model.

Circadian actions of orexins on the retinorecipient lateral geniculate complex in rat.

KEY POINTS: Rhythmic processes in living organisms are controlled by biological clocks. The orexinergic system of the lateral hypothalamus carries circadian information to provide arousal for the brain during the active phase. Here, we show that orexins exert an excitatory action in three parts of the lateral geniculate nucleus (LGN), in particular upon directly retinorecipient neurons in the non-image forming visual structures. We provide evidence for the high nocturnal levels of orexins with stable circadian expression of predominant orexin receptor 2 in the LGN. Our data additionally establish the convergence of orexinergic and pituitary adenylate cyclase (PAC)-activating peptide/PAC1 receptor systems (used by melanopsin-expressing retinal ganglion cells), which directly regulates responses to the retinal input. These results help us better understand circadian orexinergic control over the non-image forming subcortical visual system, forming the animal's preparedness for the behaviourally active night. ABSTRACT: The orexinergic system of the lateral hypothalamus is tightly interlinked with the master circadian clock and displays daily variation in activity to provide arousal-related excitation for the plethora of brain structures in a circadian manner. Here, using a combination of electrophysiological, optogenetic, histological, molecular and neuronal tracing methods, we explore a particular link between orexinergic and visual systems in rat. The results of the present study demonstrate that orexinergic fibre density at the area of subcortical visual system exerts a clear day to night variability, reaching a maximum at behaviourally active night. We also show pronounced electrophysiological activations of neurons in the lateral geniculate nucleus by orexin A through 24 h, via identified distinct orexin receptors, with the ventrolateral geniculate displaying a daily cycle of responsiveness. In addition, for the first time, we provide a direct evidence for orexins to act on retinorecipient neurons with a high convergence of orexinergic and putatively retinal pituitary adenylate cyclase (PAC)-activating peptide/PAC1 receptor systems. Altogether, the present study ties orexins to non-image forming visual structures with implications for circadian orexinergic modulation of neurons, which process information on ambient light levels.

Mapping the human lateral geniculate nucleus and its cytoarchitectonic subdivisions using quantitative MRI.

The human lateral geniculate nucleus (LGN) of the visual thalamus is a key subcortical processing site for visual information analysis. Due to its small size and deep location within the brain, a non-invasive characterization of the LGN and its microstructurally distinct magnocellular (M) and parvocellular (P) subdivisions in humans is challenging. Here, we investigated whether structural quantitative MRI (qMRI) methods that are sensitive to underlying microstructural tissue features enable MR-based mapping of human LGN M and P subdivisions. We employed high-resolution 7 Tesla in-vivo qMRI in N = 27 participants and ultra-high resolution 7 Tesla qMRI of a post-mortem human LGN specimen. We found that a quantitative assessment of the LGN and its subdivisions is possible based on microstructure-informed qMRI contrast alone. In both the in-vivo and post-mortem qMRI data, we identified two components of shorter and longer longitudinal relaxation time (T1) within the LGN that coincided with the known anatomical locations of a dorsal P and a ventral M subdivision, respectively. Through ground-truth histological validation, we further showed that the microstructural MRI contrast within the LGN pertains to cyto- and myeloarchitectonic tissue differences between its subdivisions. These differences were based on cell and myelin density, but not on iron content. Our qMRI-based mapping strategy paves the way for an in-depth understanding of LGN function and microstructure in humans. It further enables investigations into the selective contributions of LGN subdivisions to human behavior in health and disease.

Intrinsic circadian timekeeping properties of the thalamic lateral geniculate nucleus.

Circadian rhythmicity in mammals is sustained by the central brain clock-the suprachiasmatic nucleus of the hypothalamus (SCN), entrained to the ambient light-dark conditions through a dense retinal input. However, recent discoveries of autonomous clock gene expression cast doubt on the supremacy of the SCN and suggest circadian timekeeping mechanisms devolve to local brain clocks. Here, we use a combination of molecular, electrophysiological, and optogenetic tools to evaluate intrinsic clock properties of the main retinorecipient thalamic center-the lateral geniculate nucleus (LGN) in male rats and mice. We identify the dorsolateral geniculate nucleus as a slave oscillator, which exhibits core clock gene expression exclusively in vivo. Additionally, we provide compelling evidence for intrinsic clock gene expression accompanied by circadian variation in neuronal activity in the intergeniculate leaflet and ventrolateral geniculate nucleus (VLG). Finally, our optogenetic experiments propose the VLG as a light-entrainable oscillator, whose phase may be advanced by retinal input at the beginning of the projected night. Altogether, this study for the first time demonstrates autonomous timekeeping mechanisms shaping circadian physiology of the LGN.

VGluT1 Deficiency Impairs Visual Attention and Reduces the Dynamic Range of Short-Term Plasticity at Corticothalamic Synapses.

The most common excitatory neurotransmitter in the central nervous system, glutamate, is loaded into synaptic vesicles by vesicular glutamate transporters (VGluTs). The primary isoforms, VGluT1 and 2, are expressed in complementary patterns throughout the brain and correlate with short-term synaptic plasticity. VGluT1 deficiency is observed in certain neurological disorders, and hemizygous (VGluT1+/-) mice display increased anxiety and depression, altered sensorimotor gating, and impairments in learning and memory. The synaptic mechanisms underlying these behavioral deficits are unknown. Here, we show that VGluT1+/- mice had decreased visual processing speeds during a sustained visual-spatial attention task. Furthermore, in vitro recordings of corticothalamic (CT) synapses revealed dramatic reductions in short-term facilitation, increased initial release probability, and earlier synaptic depression in VGluT1+/- mice. Our electron microscopy results show that VGluT1 concentration is reduced at CT synapses of hemizygous mice, but other features (such as vesicle number and active zone size) are unchanged. We conclude that VGluT1-haploinsuficiency decreases the dynamic range of gain modulation provided by CT feedback to the thalamus, and this deficiency contributes to the observed attentional processing deficit. We further hypothesize that VGluT1 concentration regulates release probability by applying a "brake" to an unidentified presynaptic protein that typically acts as a positive regulator of release.

Single-cell transcriptomics of the developing lateral geniculate nucleus reveals insights into circuit assembly and refinement.

Coordinated changes in gene expression underlie the early patterning and cell-type specification of the central nervous system. However, much less is known about how such changes contribute to later stages of circuit assembly and refinement. In this study, we employ single-cell RNA sequencing to develop a detailed, whole-transcriptome resource of gene expression across four time points in the developing dorsal lateral geniculate nucleus (LGN), a visual structure in the brain that undergoes a well-characterized program of postnatal circuit development. This approach identifies markers defining the major LGN cell types, including excitatory relay neurons, oligodendrocytes, astrocytes, microglia, and endothelial cells. Most cell types exhibit significant transcriptional changes across development, dynamically expressing genes involved in distinct processes including retinotopic mapping, synaptogenesis, myelination, and synaptic refinement. Our data suggest that genes associated with synapse and circuit development are expressed in a larger proportion of nonneuronal cell types than previously appreciated. Furthermore, we used this single-cell expression atlas to identify the Prkcd-Cre mouse line as a tool for selective manipulation of relay neurons during a late stage of sensory-driven synaptic refinement. This transcriptomic resource provides a cellular map of gene expression across several cell types of the LGN, and offers insight into the molecular mechanisms of circuit development in the postnatal brain.

Developmental Remodeling of Thalamic Interneurons Requires Retinal Signaling.

The dorsal lateral geniculate nucleus (dLGN) of the mouse is a model system to study the development of thalamic circuitry. Most studies focus on relay neurons of dLGN, yet little is known about the development of the other principal cell type, intrinsic interneurons. Here we examined whether the structure and function of interneurons relies on retinal signaling. We took a loss-of-function approach and crossed GAD67-GFP mice, which express GFP in dLGN interneurons, with math5 nulls (math5-/-), mutants that lack retinal ganglion cells and retinofugal projections. In vitro recordings and 3-D reconstructions of biocytin-filled interneurons at different postnatal ages showed their development is a multistaged process involving migration, arbor remodeling, and synapse formation. Arbor remodeling begins during the second postnatal week, after migration to and dispersion within dLGN is complete. This phase includes a period of exuberant branching where arbors grow in number, complexity, and field size. Such growth is followed by branch pruning and stabilization, as interneurons adopt a bipolar architecture. The absence of retinal signaling disrupts this process. The math5-/- interneurons fail to branch and prune, and instead maintain a simple, sparse architecture. To test how such defects influence connectivity with dLGN relay neurons, we used DHPG [(RS)-3,5-dihydroxyphenylglycine], the mGluR1,5 agonist that targets F2 terminals. This led to substantial increases in IPSC activity among WT relay neurons but had little impact in math5-/- mice. Together, these data suggest that retinal signaling is needed to support the arbor elaboration and synaptic connectivity of dLGN interneurons.SIGNIFICANCE STATEMENT Presently, our understanding about the development of the dorsal lateral geniculate nucleus is limited to circuits involving excitatory thalamocortical relay neurons. Here we show that the other principal cell type, intrinsic interneurons, has a multistaged developmental plan that relies on retinal innervation. These findings indicate that signaling from the periphery guides the maturation of interneurons and the establishment of inhibitory thalamic circuits.

Feedforward Thalamocortical Connectivity Preserves Stimulus Timing Information in Sensory Pathways.

Reliable timing of cortical spikes in response to visual events is crucial in representing visual inputs to the brain. Spikes in the primary visual cortex (V1) need to occur at the same time within a repeated visual stimulus. Two classical mechanisms are employed by the cortex to enhance reliable timing. First, cortical neurons respond reliably to a restricted set of stimuli through their preference for certain patterns of membrane potential due to their intrinsic properties. Second, intracortical networking of excitatory and inhibitory neurons induces lateral inhibition that, through the timing and strength of IPSCs and EPSCs, produces sparse and reliably timed cortical neuron spike trains to be transmitted downstream. Here, we describe a third mechanism that, through preferential thalamocortical synaptic connectivity, enhances the trial-to-trial timing precision of cortical spikes in the presence of spike train variability within each trial that is introduced between LGN neurons in the retino-thalamic pathway. Applying experimentally recorded LGN spike trains from the anesthetized cat to a detailed model of a spiny stellate V1 neuron, we found that output spike timing precision improved with increasing numbers of convergent LGN inputs. The improvement was consistent with the predicted proportionality of [Formula: see text] for n LGN source neurons. We also found connectivity configurations that maximize reliability and that generate V1 cell output spike trains quantitatively similar to the experimental recordings. Our findings suggest a general principle, namely intra-trial variability among converging inputs, that increases stimulus response precision and is widely applicable to synaptically connected spiking neurons.SIGNIFICANCE STATEMENT The early visual pathway of the cat is favorable for studying the effects of trial-to-trial variability of synaptic inputs and intra-trial variability of thalamocortical connectivity on information transmission into the visual cortex. We have used a detailed model to show that there are preferred combinations of the number of thalamic afferents and the number of synapses per afferent that maximize the output reliability and spike-timing precision of cortical neurons. This provides additional insights into how synchrony in thalamic spike trains can reduce trial-to-trial variability to produce highly reliable reporting of sensory events to the cortex. The same principles may apply to other converging pathways where temporally jittered spike trains can reliably drive the downstream neuron and improve temporal precision.

Fractal spike dynamics and neuronal coupling in the primate visual system.

KEY POINTS: We measured fractal (self-similar) fluctuations in ongoing spiking activity in subcortical (lateral geniculate nucleus, LGN) and cortical (area MT) visual areas in anaesthetised marmosets. Cells in the evolutionary ancient koniocellular LGN pathway and in area MT show high-amplitude fractal fluctuations, whereas evolutionarily newer parvocellular and magnocellular LGN cells do not. Spiking activity in koniocellular cells and MT cells shows substantial correlation to the local population activity, whereas activity in parvocellular and magnocellular cells is less correlated with local activity. We develop a model consisting of a fractal process and a global rate modulation which can reproduce and explain the fundamental relationship between fractal fluctuations and population coupling in LGN and MT. The model provides a unified account of apparently disparate aspects of neural spiking activity and can improve our understanding of information processing in evolutionary ancient and modern visual pathways. ABSTRACT: The brain represents and processes information through patterns of spiking activity, which is influenced by local and widescale brain circuits as well as intrinsic neural dynamics. Whether these influences have independent or linked effects on spiking activity is, however, not known. Here we measured spiking activity in two visual centres, the lateral geniculate nucleus (LGN) and cortical area MT, in marmoset monkeys. By combining the Fano-factor time curve, power spectral analysis and rescaled range analysis, we reveal inherent fractal fluctuations of spiking activity in LGN and MT. We found that the evolutionary ancient koniocellular (K) pathway in LGN and area MT exhibits strong fractal fluctuations at short (<1 s) time scales. Parvocellular (P) and magnocellular (M) LGN cells show weaker fractal fluctuations at longer (multi-second) time scales. In both LGN and MT, the amplitude and time scale of fractal fluctuations can explain short and long time scale spiking dynamics. We further show differential neuronal coupling of LGN and MT cells to local population spiking activity. The population coupling is intrinsically linked to fractal fluctuations: neurons showing stronger fluctuations are more strongly correlated to the local population activity. To understand this relationship, we modelled spiking activity using a fractal inhomogeneous Poisson process with dynamic rate, which is the product of an intrinsic stochastic fractal rate and a global modulatory gain. Our model explains the intrinsic links between neuronal spike rate and population coupling in LGN and MT, and establishes a unified account of dynamic spiking properties in afferent visual pathways.

Synaptic properties of the feedback connections from the thalamic reticular nucleus to the dorsal lateral geniculate nucleus.

The thalamic reticular nucleus (TRN) is a shell-like structure comprised of GABAergic neurons that surrounds the dorsal thalamus. While playing a key role in modulating thalamocortical interactions, TRN inhibition of thalamic activity is often thought of as having an all-or-none impact. Although TRN neurons have a dynamic firing range, it remains unclear how variable rates of TRN activity gate thalamocortical transmission. To address this, we examined the ultrastructural features and functional synaptic properties of the feedback connections in the mouse thalamus between TRN and the dorsal lateral geniculate nucleus (dLGN), the principal relay of retinal signals to visual cortex. Using electron microscopy to identify TRN input to dLGN, we found that TRN terminals formed synapses with non-GABAergic postsynaptic profiles. Compared with other nonretinal terminals in dLGN, those from TRN were relatively large and tended to contact proximal regions of relay cell dendrites. To evoke TRN activity in dLGN, we adopted an optogenetic approach by expressing ChR2, or a variant (ChIEF) in TRN terminals. Both in vitro and in vivo recordings revealed that repetitive stimulation of TRN terminals led to a frequency-dependent inhibition of dLGN activity, with higher rates of stimulation resulting in increasing levels of membrane hyperpolarization and corresponding decreases in spike firing. This relationship suggests that alterations in TRN activity lead to graded changes in relay cell spike firing.NEW & NOTEWORTHY The thalamic reticular nucleus (TRN) modulates thalamocortical transmission through inhibition. In mouse, TRN terminals in the dorsal lateral geniculate nucleus (dLGN) form synapses with relay neurons but not interneurons. Stimulation of TRN terminals in dLGN leads to a frequency-dependent form of inhibition, with higher rates of stimulation leading to a greater suppression of spike firing. Thus, TRN inhibition appears more dynamic than previously recognized, having a graded rather than an all-or-none impact on thalamocortical transmission.