Single-cell spatial transcriptome reveals cell-type organization in the macaque cortex.

Elucidating the cellular organization of the cerebral cortex is critical for understanding brain structure and function. Using large-scale single-nucleus RNA sequencing and spatial transcriptomic analysis of 143 macaque cortical regions, we obtained a comprehensive atlas of 264 transcriptome-defined cortical cell types and mapped their spatial distribution across the entire cortex. We characterized the cortical layer and region preferences of glutamatergic, GABAergic, and non-neuronal cell types, as well as regional differences in cell-type composition and neighborhood complexity. Notably, we discovered a relationship between the regional distribution of various cell types and the region's hierarchical level in the visual and somatosensory systems. Cross-species comparison of transcriptomic data from human, macaque, and mouse cortices further revealed primate-specific cell types that are enriched in layer 4, with their marker genes expressed in a region-dependent manner. Our data provide a cellular and molecular basis for understanding the evolution, development, aging, and pathogenesis of the primate brain.

Effects of acute high intraocular pressure on red-green and blue-yellow cortical color responses in non-human primates.

Glaucoma is a leading cause of irreversible blindness worldwide, and intraocular pressure (IOP) is an established and modifiable risk factor for both chronic and acute glaucoma. The relationship between color vision deficits and chronic glaucoma has been described previously. However, the effects of acute glaucoma or acute primary angle closure, which has high prevalence in China, on color vision remains unclear. To address the above question, red-green or blue-yellow color responses in V1, V2, and V4 of seven rhesus macaques were monitored using intrinsic-signal optical imaging while monocular anterior chamber perfusions were performed to reversibly elevate IOP acutely over a clinically observed range of 30 to 90 mmHg. We found that the cortical population responses to both red-green and blue-yellow grating stimuli, systematically decreased as IOP increased from 30 to 90 mmHg. Although a similar decrement in magnitude was noted in V1, V2, and V4, blue-yellow responses were consistently more impaired than red-green responses at all levels of acute IOP elevation and in all monitored visual areas. This physiological study in non-human primates demonstrates that acute IOP elevations substantially depress the ability of the visual cortex to register color information. This effect is more severe for blue-yellow responses than for red-green responses, suggesting selective impairment of the koniocellular pathways compared with the parvocellular pathways. Together, we infer that blue-yellow color vision might be the most vulnerable visual function in acute glaucoma patients.

Transduction catalysis: Doxorubicin amplifies rAAV-mediated gene expression in the cortex of higher-order vertebrates.

Rapid and efficient gene transduction via recombinant adeno-associated viruses (rAAVs) is highly desirable across many basic and clinical research domains. Here, we report that vector co-infusion with doxorubicin, a clinical anti-cancer drug, markedly enhanced rAAV-mediated transgene expression in the cerebral cortex across mammalian species (cat, mouse, and macaque), acting throughout the time period examined and detectable at just three days after transfection. This enhancement showed serotype generality, being common to all rAAV serotypes tested (2, 8, 9, and PHP.eB) and was observed both locally and at remote locations consistent with doxorubicin undergoing retrograde axonal transport. All these effects were observed at doses matching human blood plasma levels in clinical therapy and lacked detectable cytotoxicity as assessed by cell morphology, activity, apoptosis, and behavioral testing. Altogether, this study identifies an effective means to improve the capability and scope of in vivo rAAV applications, amplifying cell transduction at doxorubicin concentrations paralleling medical practice.

Immediate Impact of Acute Elevation of Intraocular Pressure on Cortical Visual Motion Processing.

Purpose: To physiologically examine the impairment of cortical sensitivity to visual motion during acute elevation of intraocular pressure (IOP). Methods: Motion processing in the cat brain is well characterized, its X and Y cell visual pathways being functionally analogous to parvocellular and magnocellular pathways in primates. Using this model, we performed ocular anterior chamber perfusion to reversibly elevate IOP over a range from 30 to 90 mm Hg while monitoring cortical activity with intrinsic signal optical imaging. Drifting random-dot fields and gratings were used to characterize cortical population responses to motion direction and orientation in early visual areas 17 and 18. Results: We found that acute IOP elevations at 50 mm Hg and above, which is often observed in acute glaucoma, suppressed cortical motion direction responses. This suppression was more profound in area 17 than in area 18, and more profound in central than peripheral visual field (eccentricities 0°-4° vs. 4°-8°) within area 17. In addition, orientation responses were more suppressed than motion direction responses for the same IOP modulation. Conclusions: In contrast to human chronic glaucoma that may cause greater dysfunction in large-cell magnocellular than in small-cell parvocellular visual pathways, our direct measurement of cortical processing networks implies that the small X-cell pathway shows greater vulnerability to acute IOP elevation than the large Y-cell pathway in visual motion processing. The results demonstrate that fine discrimination mechanisms for motion in the central visual field are particularly impacted by acute IOP attacks, suggesting a neural basis for immediate visual deficits in the fine motion perception of acute glaucoma patients.

Impact of acute intraocular pressure elevation on the visual acuity of non-human primates.

BACKGROUND: Glaucoma is the leading cause of irreversible blindness worldwide and elevated intraocular pressure (IOP) is an established risk factor. Visual acuity, the capacity for fine analysis of spatial frequency (SF) information, is relatively preserved in central vision until the later stages of chronic glaucoma. However, for acute glaucoma that is associated with sharp IOP elevation, how visual acuity is affected by acute IOP elevation remains unclear. METHODS: Using intrinsic-signal optical imaging of large areas of visual cortices V1 and V2 in seven rhesus macaques, visual acuity was directly examined during acute IOP elevation at 70 mmHg, a pressure often observed in acute angle-closure glaucoma. Acute IOP elevation was achieved by reversible monocular anterior chamber perfusions, and visual acuity was quantified by cortical population responses to various SFs ranging from 0.5-6 cycles/°. FINDINGS: Acute IOP elevation particularly depressed the ability of the visual cortex to register fine details (at high SFs referring to visual acuity), an effect that was progressively more severe toward the central visual field. These results completely contrast with long-term impairments present in chronic glaucoma. INTERPRETATION: Our results show that impairment of fine visual discrimination within the central visual field is the principal consequence of sharp IOP elevation, implicating relatively greater dysfunction in parvocellular pathways. This study provides direct cortical neural evidence for the immediate visual acuity impairment in acute glaucoma patients. FUND: National Natural Science Foundation of China, Chinese Academy of Sciences, Shanghai Committee of Science and Technology, and Shanghai Municipal Health Commission.

Neuronal basis of perceptual learning in striate cortex.

It is well known that, in humans, contrast sensitivity training at high spatial frequency (SF) not only leads to contrast sensitivity improvement, but also results in an improvement in visual acuity as assessed with gratings (direct effect) or letters (transfer effect). However, the underlying neural mechanisms of this high spatial frequency training improvement remain to be elucidated. In the present study, we examined four properties of neurons in primary visual cortex (area 17) of adult cats that exhibited significantly improved acuity after contrast sensitivity training with a high spatial frequency grating and those of untrained control cats. We found no difference in neuronal contrast sensitivity or tuning width (Width) between the trained and untrained cats. However, the trained cats showed a displacement of the cells' optimal spatial frequency (OSF) to higher spatial frequencies as well as a larger neuronal signal-to-noise ratio (SNR). Furthermore, both the neuronal differences in OSF and SNR were significantly correlated with the improvement of acuity measured behaviorally. These results suggest that striate neurons might mediate the perceptual learning-induced improvement for high spatial frequency stimuli by an alteration in their spatial frequency representation and by an increased SNR.

Acute alcohol exposure impairs neural representation of visual motion speed in the visual cortex area posteromedial lateral suprasylvian cortex of cats.

BACKGROUND: Psychophysical and behavioral studies have demonstrated that perception of motion can be impaired by acute alcohol exposure. The neural activities of posteromedial lateral suprasylvian cortex (PMLS) of cats are directly linked to the perception of visual motion speed. To date, there have been no studies on the effects of acute alcohol exposure in vivo upon the representation of speed in PMLS neurons. METHODS: Alcohol was administered intravenously as a 20% (v/v) saline solution via a syringe at a dose levels of 0.5, 1, or 2 g/kg to generate a series of blood alcohol concentrations. Using extracellular single-unit recording technique, we recorded the speed-tuning properties of PMLS neurons that responded to random-dot patterns before and after alcohol administration, and simultaneously monitored the concentration of ethanol by detecting the breath alcohol concentration using a breath analyzer. RESULTS: After acute alcohol treatment, PMLS cells preferred lower speeds. A broadened speed-tuning bandwidth of PMLS cells was also observed after acute alcohol administration. Additionally, response modulation and discriminative capacity for speed of visual motion in the PMLS cells were significantly impaired after acute alcohol exposure. Concurrently, PMLS cells after acute alcohol exposure showed decreased spontaneous activity, peak responses, and signal-to-noise ratios. CONCLUSIONS: There is a significant functional degradation in the neural representation of visual motion speed in PMLS of cats after acute alcohol exposure. These neural changes may contribute to the alcohol-related deficits in visual motion perception observed in behavioral studies.

Form-cue invariant second-order neuronal responses to contrast modulation in primate area V2.

A fundamental task of the visual system is to extract figure-ground boundaries between images of objects, which in natural scenes are often defined not only by luminance differences but also by "second-order" contrast or texture differences. Responses to contrast modulation (CM) and other second-order stimuli have been extensively studied in human psychophysics, but the neuronal substrates of second-order responses in nonhuman primates remain poorly understood. In this study, we have recorded single neurons in area V2 of macaque monkeys, using both CM patterns as well as conventional luminance modulation (LM) gratings. CM stimuli were constructed from stationary sine wave grating carrier patterns, which were modulated by drifting envelope gratings of a lower spatial frequency. We found approximately one-third of visually responsive V2 neurons responded to CM stimuli with a pronounced selectivity to carrier spatial frequencies, and often orientations, that were clearly outside the neurons' passbands for LM gratings. These neurons were "form-cue invariant" in that their tuning to CM envelope spatial frequency and orientation was very similar to that for LM gratings. Neurons were tuned to carrier spatial frequencies that were typically 2-4 octaves higher than their optimal envelope spatial frequencies, similar to results from human psychophysics. These results are distinct from CM responses arising from surround suppression, but could be understood in terms of a filter-rectify-filter model. Such neurons could provide a functionally useful and explicit representation of segmentation boundaries as well as a plausible neural substrate for human perception of second-order boundaries.

Declined contrast sensitivity of neurons along the visual pathway in aging cats.

Changes in the visual cortex appear to mediate much of the visual degradation during normal aging. However, how aging affects different stages along the visual pathway is unclear. In the current study, the contrast response function, one of the most important properties of neurons from early visual areas to high brain areas, was systematically compared along the visual pathway, including the lateral geniculate nucleus (LGN), early visual cortices (A17 and A18), and posteromedial lateral suprasylvian cortex (PMLS, analog to the medial temporal area (MT) in monkeys) of young and old cats. We found that the effects of aging on the LGN were negligible, whereas those in the striate cortex were substantial, with even more severe degradation in the PMLS. Reduced contrast sensitivity of neurons in the three cortical areas was accompanied by enhanced maximal visual response, increased spontaneous activity, and decreased signal-to-noise ratio, while LGN neurons exhibited largely normal response properties. Our results suggested that there was a progressively greater effect of aging on neurons at successively higher stages in the visual pathway.

Changes of spatial and temporal frequency tuning properties of neurons in the middle temporal area of aged rhesus monkeys.

Aged humans exhibit severe deficits in visual motion perception and contrast sensitivity under various levels of spatial and temporal modulation. Previous studies indicated that many of these deficits are probably mediated by the neural degradation of the central visual system. To clarify the neuronal response mechanisms underlying the visual degradation during aging, we examined the spatial and temporal frequency tuning properties of neurons from anesthetised and paralysed aged monkeys at the middle temporal area (area MT), which is downstream of the primary visual cortex in the visual processing pathway and thought to be critical for motion perception. We found that the preferred spatial and temporal frequencies, spatial resolution and high temporal frequency cutoff of area MT neurons were reduced in aged monkeys, and were accompanied by the broadened tuning width of spatial frequency, elevated spontaneous activity, and decreased signal-to-noise ratio. These results showed that, for neurons in area MT, aging significantly changed both the spatial and temporal frequency response tuning properties. Such evidence provides new insight into the changes occurring at the electrophysiological level that may be related to the aging-related visual deficits, especially in processing spatial and temporal information.

[Aging affects on the response irregularity of cells in different visual areas of cats].

In this research, we compared the visual neuron responses for LGN, A18 and PMLS of old and young cats with extracellular single-neuron recording techniques. We used firing rate vector to characterize information, and response irregularity of cells to evaluate the degeneration of visual characters. Response irregularity is characterized by means of the two coefficients of variation of firing rate vectors: Cv and Cv2. We found that there was no significant change of the response irregularity in LGN areas during the aging process from young to old cats. But in the other two areas, neurons of old cats exhibited significantly larger response irregularity than those of young cats. The result indicated that the information processing function of advanced visual cortex was impaired by aging. This result also provids a reference for the research of the other neuronal system changes during aging process.