Developing optogenetics in non-human primates (NHPs) is essential for translating its successful implementation in rodents to clinical applications in humans. However, information about how optogenetics influences the primate cortex remains limited. Here, we evaluate how optogenetic stimulation of the primate primary visual cortex (V1) affects local and large-scale network activation concerned with visual perception. To this end we injected an optogenetic construct (AAV9-hSyn-ChR2-eYFP) into the V1 cortex of four macaque monkeys (macaca mulatta) and measured the effects of optogenetic V1 stimulation using functional magnetic resonance imaging (fMRI), laminar electrophysiology, and behavioural assessment. In three macaques, blood-oxygen-dependent (BOLD) fMRI activity could be reliably elicited with optogenetic stimulation in V1 and several connected extrastriate brain areas, including V2/V3, motion-sensitive area MT and the frontal-eye-fields (FEF), in particular when pulsed stimulation at 40 Hz was applied. BOLD modulation was associated with consistent neural spiking activity measured in V1 of two macaques. More detailed analysis revealed strongest neuronal activation in layer 4B and infragranular layers, which tightly reflected the histological expression pattern of the optogenetic construct in V1. Driving this visual network proved sufficient to elicit a visual percept (phosphene) in one macaque during a perceptual choice task. Taken together, our findings reveal the laminar and large-cortical activation pattern related to visual phosphene generation and emphasize the need for further improving optogenetic methods in NHPs as a step towards applications in humans.

Hippocampal place cells are known to have a key role in encoding spatial information. Aversive stimuli, such as predator odor, evoke place field remapping and a change in preferred firing locations. However, it remains unclear how place cells use positive or negative experiences to remap. We investigated whether CA1 place cells, recorded from behaving rats, remap randomly or whether their reconfiguration depends on the perceived location of the aversive stimulus. Exposure to trimethylthiazoline (TMT; an innately aversive odor), increased the amplitude of hippocampal β oscillations in the two arms of the maze in which TMT exposure occurred. We found that a population of place cells with fields located outside the TMT arms increased their activity (extrafield spiking) in the TMT arms during the aversive episodes. Moreover, in the subsequent post-TMT recording, these cells exhibited a significant shift in their center of mass (COM) towards the TMT arms. The induction of extrafield plasticity was mediated by the basolateral amygdala complex (BLA). Photostimulation of the BLA triggered aversive behavior, synchronized hippocampal local field oscillations, and increased the extrafield spiking of the hippocampal place cells for the first 100 ms after light delivery. Optogenetic BLA activation triggered an increase in extrafield spiking activity that was correlated with the degree of place field plasticity. Furthermore, BLA-mediated increase of the extrafield activity predicts the degree of subsequent field plasticity. Our findings demonstrate that that the remapping of hippocampal place cells during aversive episodes is not random but it depends on the location of the aversive stimulus.

27The hippocampal place cells encode spatial representation but it remains unclear how they store 28 concurrent positive or negative experiences. Here, we report on place field reconfiguration in 29 response to an innately aversive odor trimethylthiazoline (TMT). The advantage of TMT is the 30 absence of learning curve required for associative fear conditioning. Our study investigated if 31 CA1 place cells, recorded from behaving rats, remap randomly or if their reconfiguration 32 depends on the location of the aversive stimulus perception. Exposure to TMT increased the 33 amplitude of hippocampal beta oscillations in two arms of a maze (TMT arms). We found that 34 a population of place cells with fields located outside the TMT arms increased their activity 35 (extra-field spiking) in the TMT arms during the aversive episodes. These cells exhibited 36 significant shift of the center of mass towards the TMT arms in the subsequent post-TMT 37 recording. The induction of extra-field plasticity was mediated by the basolateral amygdala 38 complex (BLA). Photostimulation of the BLA triggered aversive behavior, synchronized 39 response of hippocampal local field oscillations, augmented theta rhythm amplitude and 40 increased the spiking of place cells for the first 100ms after the light delivery. This occurred 41only for the extra-field-but not for intra-field spikes. Optogenetic BLA-triggered an increase 42 in extra-field spiking activity correlated to the degree of place field plasticity in the post-ChR2 43 recording session. Our findings demonstrate that the increased extra-field activity during 44 aversive episodes mediates the degree of subsequent field plasticity. 45 46 47 48 49 50 Introduction 51Hippocampus temporally encodes representations of spatial context-dependent experiences 52 (Knierim, 2003) and these memory traces are functionally strengthened in the cortical areas for 53 long-term recollection (Nadel and Moscovitch, 1997; Kitamura et al., 2009; Tayler et al., 2013; 54 Denny et al., 2014). Current theories propose that memory of spatial location is encoded by 55 hippocampal place cells (O'Keefe and Nadel, 1978), but there is scarce information how these 56 neurons encode non-spatial information such as aversive episodes. We know that aversion 57 evokes place field remapping (Moita et al., 2004; Kim et al., 2015) where a subset of neurons 58 in hippocampal area CA1 change their preferred firing locations in response to predator odor 59 (Wang et al., 2012). However, it is still unclear which neurons remap to encode fearful 60 experience and which neurons preserve their spatial fields. Here, we examined the principles 61 governing aversion-induced place field remapping. We tested the hypothesis that the place cells 62 remapping depends on the spatial location of the aversive stimulus perception. The evaluation 63 of change of place field center of mass (ΔCOM) is the most sensitive indicator of experience-64 dependent place field place field reconfiguration (Mehta et al., 1997; Knierim, 2002; Lee et a...

A growing body of psychophysical research reports theta (3-8 Hz) rhythmic fluctuations in visual perception that are often attributed to an attentional sampling mechanism arising from theta rhythmic neural activity in mid- to high-level cortical association areas. However, it remains unclear to what extent such neuronal theta oscillations might already emerge at early sensory cortex like the primary visual cortex (V1), e.g. from the stimulus filter properties of neurons. To address this question, we recorded multi-unit neural activity from V1 of two macaque monkeys viewing a static visual stimulus with variable sizes, orientations and contrasts. We found that among the visually responsive electrode sites, more than 50 % showed a spectral peak at theta frequencies. Theta power varied with varying basic stimulus properties. Within each of these stimulus property domains (e.g. size), there was usually a single stimulus value that induced the strongest theta activity. In addition to these variations in theta power, the peak frequency of theta oscillations increased with increasing stimulus size and also changed depending on the stimulus position in the visual field. Further analysis confirmed that this neural theta rhythm was indeed stimulus-induced and did not arise from small fixational eye movements (microsaccades). When the monkeys performed a detection task of a target embedded in a theta-generating visual stimulus, reaction times also tended to fluctuate at the same theta frequency as the one observed in the neural activity. The present study shows that a highly stimulus-dependent neuronal theta oscillation can be elicited in V1 that appears to influence the temporal dynamics of visual perception.

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