Serotonin, an important neuromodulator in the brain, is implicated in affective and cognitive functions. However, its role even for basic cortical processes is controversial. For example, in the mammalian primary visual cortex (V1), heterogenous serotonergic modulation has been observed in anesthetized animals. Here, we combined extracellular single-unit recordings with iontophoresis in awake animals. We examined the role of serotonin on well-defined tuning properties (orientation, spatial frequency, contrast, and size) in V1 of two male macaque monkeys. We find that in the awake macaque the modulatory effect of serotonin is surprisingly uniform: it causes a mainly multiplicative decrease of the visual responses and a slight increase in the stimulus-selective response latency. Moreover, serotonin neither systematically changes the selectivity or variability of the response, nor the interneuronal correlation unexplained by the stimulus (“noise-correlation”). The modulation by serotonin has qualitative similarities with that for a decrease in stimulus contrast, but differs quantitatively from decreasing contrast. It can be captured by a simple additive change to a threshold-linear spiking nonlinearity. Together, our results show that serotonin is well suited to control the response gain of neurons in V1 depending on the animal's behavioral or motivational context, complementing other known state-dependent gain-control mechanisms.SIGNIFICANCE STATEMENT Serotonin is an important neuromodulator in the brain and a major target for drugs used to treat psychiatric disorders. Nonetheless, surprisingly little is known about how it shapes information processing in sensory areas. Here we examined the serotonergic modulation of visual processing in the primary visual cortex of awake behaving macaque monkeys. We found that serotonin mainly decreased the gain of the visual responses, without systematically changing their selectivity, variability, or covariability. This identifies a simple computational function of serotonin for state-dependent sensory processing, depending on the animal's affective or motivational state.

During perceptual decisions, subjects often rely more strongly on early, rather than late, sensory evidence, even in tasks when both are equally informative about the correct decision. This early psychophysical weighting has been explained by an integration-to-bound decision process, in which the stimulus is ignored after the accumulated evidence reaches a certain bound, or confidence level. Here, we derive predictions about how the average temporal weighting of the evidence depends on a subject's decision confidence in this model. To test these predictions empirically, we devised a method to infer decision confidence from pupil size in 2 male monkeys performing a disparity discrimination task. Our animals' data confirmed the integration-to-bound predictions, with different internal decision bounds and different levels of correlation between pupil size and decision confidence accounting for differences between animals. However, the data were less compatible with two alternative accounts for early psychophysical weighting: attractor dynamics either within the decision area or due to feedback to sensory areas, or a feedforward account due to neuronal response adaptation. This approach also opens the door to using confidence more broadly when studying the neural basis of decision making. An animal's ability to adjust decisions based on its level of confidence, sometimes referred to as "metacognition," has generated substantial interest in neuroscience. Here, we show how measurements of pupil diameter in macaques can be used to infer their confidence. This technique opens the door to more neurophysiological studies of confidence because it eliminates the need for training on behavioral paradigms to evaluate confidence. We then use this technique to test predictions from competing explanations of why subjects in perceptual decision making often rely more strongly on early evidence: the way in which the strength of this effect should depend on a subject's decision confidence. We find that a bounded decision formation process best explains our empirical data.

During perceptual decisions subjects often rely more strongly on early rather than late 21 sensory evidence even in tasks when both are equally informative about the correct 22 decision. This early psychophysical weighting has been explained by an integration-to-23 bound decision process, in which the stimulus is ignored after the accumulated evidence 24 reaches a certain bound, or confidence level. Here, we derive predictions about how the 25 average temporal weighting of the evidence depends on a subject's decision-confidence 26 in this model. To test these predictions empirically, we devised a method to infer 27 decision-confidence from pupil size in monkeys performing a disparity discrimination 28 task. Our animals' data confirmed the integration-to-bound predictions, with different 29 internal decision-bounds accounting for differences between animals. However, the data 30 could not be explained by two alternative accounts for early psychophysical weighting: 31 attractor dynamics either within the decision area or due to feedback to sensory areas, or 32 a feedforward account due to neuronal response adaptation. This approach also opens 33 the door to using confidence more broadly when studying the neural basis of decision-34 making. 35 36 37 measuring the animal's subjective decision confidence. 54 55Measuring decision confidence psychophysically is relatively difficult, particularly in animals, and 56 increases the complexity of a task, as e.g. for post-decision wagering 12,13 , hence requiring 57 additional training. To avoid these difficulties we devised a metric based on the monkeys' pupil 58 size. Combining this metric for decision confidence with psychophysical reverse correlation 3,14,15 59 allowed us to quantify the animals' psychophysical weighting strategy for different levels of 60 inferred decision-confidence, and test our model predictions. The animals showed clear early 61 psychophysical weighting on average. But separating this analysis by inferred decision 62 confidence revealed that early psychophysical weighting was largely restricted to high 63 confidence trials. In fact, on low inferred confidence trials the animals weighted the stimulus 64 relatively uniformly or even slightly more towards the end of the trial. Such behavior matched 65 the predictions of the integration-to-bound model. Furthermore, the differences between both 66 animals could be accounted for by the model by differences in the only free parameter -their 67 internal decision-bound. 68 69In contrast, the animals' behavior could not be fully explained by two alternative accounts of 70 early psychophysical weighting. The first alternative account are models in which the decision-71 3 stage provides self-reinforcing feedback to the sensory neurons 16 , as suggested, e.g. for 72 probabilistic inference 17 , or by attractor dynamics within the decision-making area 28 . The 73 second, recent alternative proposal is that the early weighting simply reflects the feed-forward 74 effect of the dynamics (gain control or adaptation) o...

Highlights 18• We developed an approach to train macaque monkeys head-free on visuomotor tasks 19 requiring measurements of eye position 20• The setup is inexpensive, easy to build, and readily adjusted to the animal without the need 21 for sedation 22 Abstract 31We describe a modified system for training macaque monkeys without invasive head 32 immobilization on visuomotor tasks requiring the control of eye-movements. The system 33 combines a conventional primate chair, a chair-mounted infrared camera for measuring 34 eye-movements and a custom-made concave reward-delivery spout firmly attached to 35 the chair. The animal was seated head-free inside the chair but the concavity of the spout 36 stabilized its head during task performance. Training on visual fixation and 37 discrimination tasks was successfully performed with this system. Eye-measurements, 38 such as fixation-precision, pupil size as well as micro-saccades were comparable to 39 those obtained using conventional invasive head-fixation methods. The system is 40 inexpensive (~$40 USD material cost), easy to fabricate in a workshop (technical 41 drawings are included), and readily adjustable between animals without the need to 42 immobilize or sedate them for these adjustments. 43 44 45

Sensory processing is influenced by neuromodulators such as serotonin, thought to relay behavioural state. Recent work has shown that the modulatory effect of serotonin itself differs with the animal's behavioural state. In primates, including humans, the serotonin system is anatomically important in the primary visual cortex (V1). We previously reported that in awake fixating macaques, serotonin reduces the spiking activity by decreasing response gain in V1. But the effect of serotonin on the local network is unknown. Here, we simultaneously recorded single-unit activity and local field potentials (LFPs) while iontophoretically applying serotonin in V1 of alert monkeys fixating on a video screen for juice rewards. The reduction in spiking response we observed previously is the opposite of the known increase of spiking activity with spatial attention. Conversely, in the local network (LFP), the application of serotonin resulted in changes mirroring the local network effects of previous reports in macaques directing spatial attention to the receptive field. It reduced the LFP power and the spike-field coherence, and the LFP became less predictive of spiking activity, consistent with reduced functional connectivity. We speculate that together, these effects may reflect the sensory side of a serotonergic contribution to quiet vigilance: The lower gain reduces the salience of stimuli to suppress an orienting reflex to novel stimuli, whereas at the network level, visual processing is in a state comparable to that of spatial attention.