Dopamine influences attentional rate modulation in Macaque posterior parietal cortex.

Cognitive neuroscience has made great strides in understanding the neural substrates of attention, but our understanding of its neuropharmacology remains incomplete. Although dopamine has historically been studied in relation to frontal functioning, emerging evidence suggests important dopaminergic influences in parietal cortex. We recorded single- and multi-unit activity whilst iontophoretically administering dopaminergic agonists and antagonists while rhesus macaques performed a spatial attention task. Out of 88 units, 50 revealed activity modulation by drug administration. Dopamine inhibited firing rates according to an inverted-U shaped dose-response curve and increased gain variability. D1 receptor antagonists diminished firing rates according to a monotonic function and interacted with attention modulating gain variability. Finally, both drugs decreased the pupil light reflex. These data show that dopamine shapes neuronal responses and modulates aspects of attentional processing in parietal cortex.

Neocortical pyramidal neurons with axons emerging from dendrites are frequent in non-primates, but rare in monkey and human.

The canonical view of neuronal function is that inputs are received by dendrites and somata, become integrated in the somatodendritic compartment and upon reaching a sufficient threshold, generate axonal output with axons emerging from the cell body. The latter is not necessarily the case. Instead, axons may originate from dendrites. The terms 'axon carrying dendrite' (AcD) and 'AcD neurons' have been coined to describe this feature. In rodent hippocampus, AcD cells are shown to be functionally 'privileged', since inputs here can circumvent somatic integration and lead to immediate action potential initiation in the axon. Here, we report on the diversity of axon origins in neocortical pyramidal cells of rodent, ungulate, carnivore, and primate. Detection methods were Thy-1-EGFP labeling in mouse, retrograde biocytin tracing in rat, cat, ferret, and macaque, SMI-32/ßIV-spectrin immunofluorescence in pig, cat, and macaque, and Golgi staining in macaque and human. We found that in non-primate mammals, 10-21% of pyramidal cells of layers II-VI had an AcD. In marked contrast, in macaque and human, this proportion was lower and was particularly low for supragranular neurons. A comparison of six cortical areas (being sensory, association, and limbic in nature) in three macaques yielded percentages of AcD cells which varied by a factor of 2 between the areas and between the individuals. Unexpectedly, pyramidal cells in the white matter of postnatal cat and aged human cortex exhibit AcDs to much higher percentages. In addition, interneurons assessed in developing cat and adult human cortex had AcDs at type-specific proportions and for some types at much higher percentages than pyramidal cells. Our findings expand the current knowledge regarding the distribution and proportion of AcD cells in neocortex of non-primate taxa, which strikingly differ from primates where these cells are mainly found in deeper layers and white matter.

Neuronal figure-ground responses in primate primary auditory cortex.

Figure-ground segregation, the brain's ability to group related features into stable perceptual entities, is crucial for auditory perception in noisy environments. The neuronal mechanisms for this process are poorly understood in the auditory system. Here, we report figure-ground modulation of multi-unit activity (MUA) in the primary and non-primary auditory cortex of rhesus macaques. Across both regions, MUA increases upon presentation of auditory figures, which consist of coherent chord sequences. We show increased activity even in the absence of any perceptual decision, suggesting that neural mechanisms for perceptual grouping are, to some extent, independent of behavioral demands. Furthermore, we demonstrate differences in figure encoding between more anterior and more posterior regions; perceptual saliency is represented in anterior cortical fields only. Our results suggest an encoding of auditory figures from the earliest cortical stages by a rate code.

Contribution of Ionotropic Glutamatergic Receptors to Excitability and Attentional Signals in Macaque Frontal Eye Field.

Top-down attention, controlled by frontal cortical areas, is a key component of cognitive operations. How different neurotransmitters and neuromodulators flexibly change the cellular and network interactions with attention demands remains poorly understood. While acetylcholine and dopamine are critically involved, glutamatergic receptors have been proposed to play important roles. To understand their contribution to attentional signals, we investigated how ionotropic glutamatergic receptors in the frontal eye field (FEF) of male macaques contribute to neuronal excitability and attentional control signals in different cell types. Broad-spiking and narrow-spiking cells both required N-methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation for normal excitability, thereby affecting ongoing or stimulus-driven activity. However, attentional control signals were not dependent on either glutamatergic receptor type in broad- or narrow-spiking cells. A further subdivision of cell types into different functional types using cluster-analysis based on spike waveforms and spiking characteristics did not change the conclusions. This can be explained by a model where local blockade of specific ionotropic receptors is compensated by cell embedding in large-scale networks. It sets the glutamatergic system apart from the cholinergic system in FEF and demonstrates that a reduction in excitability is not sufficient to induce a reduction in attentional control signals.

Cell class-specific modulation of attentional signals by acetylcholine in macaque frontal eye field.

Attention is critical to high-level cognition, and attentional deficits are a hallmark of cognitive dysfunction. A key transmitter for attentional control is acetylcholine, but its cellular actions in attention-controlling areas remain poorly understood. Here we delineate how muscarinic and nicotinic receptors affect basic neuronal excitability and attentional control signals in different cell types in macaque frontal eye field. We found that broad spiking and narrow spiking cells both require muscarinic and nicotinic receptors for normal excitability, thereby affecting ongoing or stimulus-driven activity. Attentional control signals depended on muscarinic, not nicotinic receptors in broad spiking cells, while they depended on both muscarinic and nicotinic receptors in narrow spiking cells. Cluster analysis revealed that muscarinic and nicotinic effects on attentional control signals were highly selective even for different subclasses of narrow spiking cells and of broad spiking cells. These results demonstrate that cholinergic receptors are critical to establish attentional control signals in the frontal eye field in a cell type-specific manner.

The Foveal Visual Representation of the Primate Superior Colliculus.

A defining feature of the primate visual system is its foveated nature. Processing of foveal retinal input is important not only for high-quality visual scene analysis but also for ensuring precise, albeit tiny, gaze shifts during high-acuity visual tasks. The representations of foveal retinal input in the primate lateral geniculate nucleus and early visual cortices have been characterized. However, how such representations translate into precise eye movements remains unclear. Here, we document functional and structural properties of the foveal visual representation of the midbrain superior colliculus. We show that the superior colliculus, classically associated with extra-foveal spatial representations needed for gaze shifts, is highly sensitive to visual input impinging on the fovea. The superior colliculus also represents such input in an orderly and very specific manner, and it magnifies the representation of foveal images in neural tissue as much as the primary visual cortex does. The primate superior colliculus contains a high-fidelity visual representation, with large foveal magnification, perfectly suited for active visuomotor control and perception.

Perceptual learning of fine contrast discrimination changes neuronal tuning and population coding in macaque V4.

Perceptual learning, the improvement in perceptual abilities with training, is thought to be mediated by an alteration of neuronal tuning. It remains poorly understood how tuning properties change as training progresses, whether improved stimulus tuning directly links to increased behavioural readout of sensory information, or how population coding mechanisms change with training. Here, we recorded continuously from multiple neuronal clusters in area V4 while macaque monkeys learned a fine contrast categorization task. Training increased neuronal coding abilities by shifting the steepest point of contrast response functions towards the categorization boundary. Population coding accuracy of difficult discriminations resulted largely from an increased information coding of individual channels, particularly for those channels that in early learning had larger ability for easy discriminations, but comparatively small encoding abilities for difficult discriminations. Population coding was also enhanced by specific changes in correlations. Neuronal activity became more indicative of upcoming choices with training.

Attention Induced Gain Stabilization in Broad and Narrow-Spiking Cells in the Frontal Eye-Field of Macaque Monkeys.

UNLABELLED: Top-down attention increases coding abilities by altering firing rates and rate variability. In the frontal eye field (FEF), a key area enabling top-down attention, attention induced firing rate changes are profound, but its effect on different cell types is unknown. Moreover, FEF is the only cortical area investigated in which attention does not affect rate variability, as assessed by the Fano factor, suggesting that task engagement affects cortical state nonuniformly. We show that putative interneurons in FEF of Macaca mulatta show stronger attentional rate modulation than putative pyramidal cells. Partitioning rate variability reveals that both cell types reduce rate variability with attention, but more strongly so in narrow-spiking cells. The effects are captured by a model in which attention stabilizes neuronal excitability, thereby reducing the expansive nonlinearity that links firing rate and variance. These results show that the effect of attention on different cell classes and different coding properties are consistent across the cortical hierarchy, acting through increased and stabilized neuronal excitability. SIGNIFICANCE STATEMENT: Cortical processing is critically modulated by attention. A key feature of this influence is a modulation of "cortical state," resulting in increased neuronal excitability and resilience of the network against perturbations, lower rate variability, and an increased signal-to-noise ratio. In the frontal eye field (FEF), an area assumed to control spatial attention in human and nonhuman primates, firing rate changes with attention occur, but rate variability, quantified by the Fano factor, appears to be unaffected by attention. Using recently developed analysis tools and models to quantify attention effects on narrow- and broad-spiking cell activity, we show that attention alters cortical state strongly in the FEF, demonstrating that its effect on the neuronal network is consistent across the cortical hierarchy.

Structure and function of the septum nasi and the underlying tension chord in crocodylians.

A long rostrum has distinct advantages for prey capture in an aquatic or semi-aquatic environment but at the same time poses severe problems concerning stability during biting. We here investigate the role of the septum nasi of brevirostrine crocodilians for load-absorption during mastication. Histologically, both the septum nasi and the septum interorbitale consist of hyaline cartilage and therefore mainly resist compression. However, we identified a strand of tissue extending longitudinally below the septum nasi that is characterized by a high content of collagenous and elastic fibers and could therefore resist tensile stresses. This strand of tissue is connected with the m. pterygoideus anterior. Two-dimensional finite element modeling shows that minimization of bending in the crocodilian skull can only be achieved if tensile stresses are counteracted by a strand of tissue. We propose that the newly identified strand of tissue acts as an active tension chord necessary for stabilizing the long rostrum of crocodilians during biting by transforming the high bending stress of the rostrum into moderate compressive stress.

Direct projections from the dorsal premotor cortex to the superior colliculus in the macaque (macaca mulatta).

The dorsal premotor cortex (PMd) is part of the cortical network for arm movements during reach-related behavior. Here we investigate the neuronal projections from the PMd to the midbrain superior colliculus (SC), which also contains reach-related neurons, to investigate how the SC integrates into a cortico-subcortical network responsible for initiation and modulation of goal-directed arm movements. By using anterograde transport of neuronal tracers, we found that the PMd projects most strongly to the deep layers of the lateral part of the SC and the underlying reticular formation corresponding to locations where reach-related neurons have been recorded, and from where descending tectofugal projections arise. A somewhat weaker projection targets the intermediate layers of the SC. By contrast, terminals originating from prearcuate area 8 mainly project to the intermediate layers of the SC. Thus, this projection pattern strengthens the view that different compartments in the SC are involved in the control of gaze and in the control or modulation of reaching movements. The PMD-SC projection assists in the participation of the SC in the skeletomotor system and provides the PMd with a parallel path to elicit forelimb movements.

Retinal ganglion cells projecting to the accessory optic system in optokinetic blind albinotic rats are direction-selective.

The optokinetic deficits in albinotic rats and ferrets are caused by the loss of direction selectivity in the accessory optic system (AOS). However, the underlying mechanisms for this loss are still not clear. Here we tested the hypothesis that, in albino rats, the retinal input to the AOS lacks direction selectivity and, as a consequence, neurons in the AOS are direction non-selective. We investigated ON-center direction-selective retinal ganglion cells, the major input to the AOS, in pigmented Long Evans and albino Wistar rats using extracellular in vitro patch-clamp techniques. To visualise putative AOS-projecting direction-selective ganglion cells, we retrogradely labeled them by injection of the infrared-sensitive dye indocyanine green into the medial terminal nucleus of the AOS. The present study is the first to present physiological evidence for retinal ON-center direction-selective ganglion cells in rat. Our results show that, in albinotic and pigmented rats, ON-center retinal ganglion cells projecting to the AOS are similarly direction-selective, suggesting that the optokinetic deficit must be caused by the abolition of direction selectivity in the AOS itself.

Contribution of cholinergic and GABAergic mechanisms to direction tuning, discriminability, response reliability, and neuronal rate correlations in macaque middle temporal area.

Previous studies have investigated the effects of acetylcholine (ACh) on neuronal tuning, coding, and attention in primary visual cortex, but its contribution to coding in extrastriate cortex is unexplored. Here we investigate the effects of ACh on tuning properties of macaque middle temporal area MT neurons and contrast them with effects of gabazine, a GABA(A) receptor blocker. ACh increased neuronal activity, it had no effect on tuning width, but it significantly increased the direction discriminability of a neuron. Gabazine equally increased neuronal activity, but it widened tuning curves and decreased the direction discriminability of a neuron. Although gabazine significantly reduced response reliability, ACh application had little effect on response reliability. Finally, gabazine increased noise correlation of simultaneously recorded neurons, whereas ACh reduced it. Thus, both drugs increased firing rates, but only ACh application improved neuronal tuning and coding in line with effects seen in studies in which attention was selectively manipulated.

Blocking retinal chloride co-transporters KCC2 and NKCC: impact on direction selective ON and OFF responses in the rat's nucleus of the optic tract.

In the present study we investigated in vivo the effects of pharmacological manipulation of retinal processing on the response properties of direction selective retinal slip cells in the nucleus of the optic tract and dorsal terminal nucleus (NOT-DTN), the key visuomotor interface in the pathway underlying the optokinetic reflex. Employing a moving visual stimulus consisting of either a large dark or light edge we could differentiate direction selective ON and OFF responses in retinal slip cells. To disclose the origin of the retinal slip cells' unexpected OFF response we selectively blocked the retinal ON channels and inactivated the visual cortex by cooling. Cortical cooling had no effect on the direction selectivity of the ON or the OFF response in NOT-DTN retinal slip cells. Blockade of the retinal ON channel with APB led to a loss of the ON and, to a lesser degree, of the OFF response and a reduction in direction selectivity. Subsequent blocking of GABA receptors in the retina with picrotoxin unmasked a vigorous albeit direction unselective OFF response in the NOT-DTN. Disturbing the retinal chloride homeostasis by intraocular injections of bumetanide or furosemide led to a loss of direction selectivity in both the NOT-DTN's ON and the OFF response due to a reduced response in the neuron's preferred direction under bumetanide as well as under furosemide and a slightly increased response in the null direction under bumetanide. Our results indicate that the direction specificity of retinal slip cells in the NOT-DTN of the rat strongly depends on direction selective retinal input which depends on intraretinal chloride homeostasis. On top of the well established input from ON center direction selective ganglion cells we could demonstrate an equally effective input from the retinal OFF system to the NOT-DTN.

Visual pathway for the optokinetic reflex in infant macaque monkeys.

The horizontal optokinetic nystagmus (hOKN) in primates is immature at birth. To elucidate the early functional state of the visual pathway for hOKN, retinal slip neurons were recorded in the nucleus of the optic tract and dorsal terminal nucleus (NOT-DTN) of 4 anesthetized infant macaques. These neurons were direction selective for ipsiversive stimulus movement shortly after birth [postnatal day 9 (P9)], although at a lower direction selectivity index (DSI). The DSI in the older infants (P12, P14, P60) was not different from adults. A total of 96% of NOT-DTN neurons in P9, P12, and P14 were binocular, however, significantly more often dominated by the contralateral eye than in adults. Already in the youngest animals, NOT-DTN neurons were well tuned to different stimulus velocities; however, tuning was truncated toward lower stimulus velocities when compared with adults. As early as at P12, electrical stimulation in V1 elicited orthodromic responses in the NOT-DTN. However, the incidence of activated neurons was much lower in infants (40-60% of the tested NOT-DTN neurons) than in adults (97%). Orthodromic latencies from V1 were significantly longer in P12-P14 (x = 12.2 ± 8.9 ms) than in adults (x = 3.51 ± 0.81 ms). At the same age, electrical stimulation in motion-sensitive area MT was more efficient in activating NOT-DTN neurons (80% of the tested cells) and yielded shorter latencies than in V1 (x = 7.8 ± 3.02 ms; adult x = 2.99 ± 0.85 ms). The differences in discharge rate between neurons in the NOT-DTN contra- and ipsilateral to the stimulated eye are equivalent to the gain asymmetry between monocularly elicited OKN in temporonasal and nasotemporal direction at the various ages.

Contrast independence of cardinal preference: stable oblique effect in orientation maps of ferret visual cortex.

The oblique effect was first described as enhanced detection and discrimination of cardinal orientations compared with oblique orientations. Such biases in visual processing are believed to originate from a functional adaptation to environmental statistics dominated by cardinal contours. At the neuronal level, the oblique orientation effect corresponds to the numerical overrepresentation and narrower tuning bandwidths of cortical neurons representing the cardinal axes. The anisotropic distribution of orientation preferences over large cortical regions was revealed with optical imaging, providing further evidence for the cortical oblique effect in several mammalian species. Our present study explores whether the dominant representation of cardinal contours persists at different stimulus contrasts. Performing intrinsic optical imaging in the ferret visual cortex and presenting drifting gratings at various orientations and contrasts (100%, 30% and 10%), we found that the overrepresentation of vertical and horizontal contours was invariant across stimulus contrasts. In addition, the responses to cardinal orientations were also more robust and evoked larger modulation depths than responses to oblique orientations. We conclude that orientation maps remain constant across the full range of contrast levels down to detection thresholds. Thus, a stable layout of the functional architecture dedicated to processing oriented edges seems to reflect a fundamental coding strategy of the early visual cortex.

Private lines of cortical visual information to the nucleus of the optic tract and dorsolateral pontine nucleus.

The subcortical nucleus of the optic tract and dorsal terminal nucleus of the accessory optic system (NOT-DTN), along with the dorsolateral pontine nucleus (DLPN), has been shown to play a pivotal role in controlling slow eye movements. Both nuclei are known to receive cortical input from striate and extrastriate cortex. To determine to what degree this cortical input arises from the same areas, and potentially from the same individual neurons, in one set of experiments we placed different retrograde tracers into the NOT-DTN and the DLPN. In the ipsilateral cortical hemisphere the two projections mainly overlapped in the middle temporal (MT) area, the middle superior temporal (MST) area, and the visual area in the fundus of the STS (FST) and the surrounding cortex. In these areas, neurons projecting to the NOT-DTN or the DLPN were closely intermingled. Nevertheless, only 3-11% of the labelled neurons in MT and MST were double-labelled in our various cases. In a second set of experiments, we identified neurons in areas MT and MST projecting to the DLPN and/or to the NOT-DTN by antidromic electrical stimulation. Again, neurons projecting to either target were located in close proximity to each other and in all subregions of MT and MST sampled. Only a small percentage of the antidromically identified projection neurons (4.4%) sent branches to both the NOT-DTN and the DLPN. On the population level, only neurons activated from the NOT-DTN had a clear preference for ipsiversive stimulus movement whereas the neurons activated from the DLPN, and neurons not antidromically activated from either target, had no common directional preference. These results indicate that the cortical input to the NOT-DTN and DLPN arises from largely separate neuronal subpopulations in the motion sensitive areas in the posterior STS. Only a small percentage of the projection neurons bifurcate to supply both targets. These findings are discussed in relation to the effects of cortical lesions on the optokinetic and smooth pursuit system.

Chromatic sensitivity of neurones in area MT of the anaesthetised macaque monkey compared to human motion perception.

We recorded activity from neurones in cortical motion-processing areas, middle temporal area (MT) and middle posterior superior temporal sulcus (MST), of anaesthetised and paralysed macaque monkeys in response to moving sinewave gratings modulated in luminance and chrominance. The activity of MT and MST neurones was highly dependent on luminance contrast. In three of four animals isoluminant chromatic modulations failed to activate MT/MST neurones significantly. At low luminance contrast a systematic dependence on chromaticity was revealed, attributable mostly to residual activity of the magnocellular pathway. Additionally, we found indications for a weak S-cone input, but rod intrusion could also have made a contribution. In contrast to the activity of MT and MST neurones, speed judgments and onset amplitude of evoked optokinetic eye movements in human subjects confronted with equivalent visual stimuli were largely independent of luminance modulation. Motion of every grating (including isoluminant) was readily visible for all but one observer. Similarity with the activity of MT/MST cells was found only for motion-nulling equivalent luminance contrast judgments at isoluminance. Our results suggest that areas MT and MST may not be involved in the processing of chromatic motion, but effects of central anaesthesia and/or the existence of intra- and inter-species differences must also be considered.

Optokinetic deficits in albino ferrets (Mustela putorius furo): a behavioral and electrophysiological study.

We compared the horizontal optokinetic reaction (OKR) and response properties of retinal slip neurons in the nucleus of the optic tract and dorsal terminal nucleus (NOT-DTN) of albino and wild-type ferrets (Mustela putorius furo). In contrast to pigmented ferrets, we were unable to observe OKR in albino ferrets during binocular and monocular viewing using random dot full field stimulation and electro-oculography (EOG). Observations during early postnatal life indicate that regular OKR is present in pigmented pups 3 d after eye opening but is absent at any stage during development in albino ferrets. Unilateral muscimol injections to inactivate all neurons in the NOT-DTN containing GABA(A) and GABA(C) receptors caused spontaneous horizontal nystagmus with slow phases away from the injected hemisphere in albino as well as in pigmented animals. Retinal slip neurons in the NOT-DTN of albino ferrets identified by antidromic activation from the inferior olive and orthodromic activation from the optic chiasm were well responding to intermittent bright light stimuli, but many showed a profound reduction of responsiveness to moving stimuli. The movement-sensitive neurons exhibited no clear direction selectivity for ipsiversive stimulus movement, a characteristic property of these neurons in pigmented ferrets and other mammals. Thus, the defect rendering albino ferrets optokinetically nonresponsive is located in the visual pathway subserving the OKR, namely in or before the NOT-DTN, and not in oculomotor centers.

Cortical projections to the nucleus of the optic tract and dorsal terminal nucleus and to the dorsolateral pontine nucleus in macaques: a dual retrograde tracing study.

The nucleus of the optic tract and dorsal terminal nucleus of the accessory optic system (NOT-DTN) along with the dorsolateral pontine nucleus (DLPN) have been shown to play a role in controlling slow eye movements and in maintaining stable vision during head movements. Both nuclei are known to receive cortical input from striate and extrastriate cortex. To determine to what degree this cortical input arises from the same areas and potentially from the same individual neurons, we placed different retrograde tracers into the NOT-DTN and the DLPN. In the ipsilateral cortical hemisphere the two projections mainly overlapped in the posterior part of the superior temporal sulcus (STS) comprising the middle temporal area (MT), the middle superior temporal area (MST), and the visual area in the fundus of the STS (FST) and the surrounding cortex. In these areas, neurons projecting to the NOT-DTN or the DLPN were closely intermingled. Nevertheless, only 3-11% of the labeled neurons in MT and MST were double-labeled in our various cases. These results indicate that the cortical input to the NOT-DTN and DLPN arises from largely separate neuronal subpopulations in the motion sensitive areas in the posterior STS. Only a small percentage of the projection neurons bifurcate to supply both targets. These findings are discussed in relation to the optokinetic and the smooth pursuit system.