Natural whisker-guided behavior by head-fixed mice in tactile virtual reality

“We next imaged neural activity in behaving mice running on a treadmill in tactile virtual reality (Sofroniew et al. 2014, Sofroniew et al. 2015).”

“…single-cell measurements of activity within 904 Neuron 94, 891–907, May 17, 2017 multiple cortical regions simultaneously, but so far this approach can only sample activity throughout the whole cortex at low frame rates ( 1 Hz) and non-synchronously (Sofroniew et al., 2014; Stirman et al., 2016).”

“Rodents can localize objects and walls under head-fixed (O’Connor et al., 2010a; Sofroniew et al., 2014) and freely moving (Hutson and Masterton, 1986; Knutsen et al.”

“A recently developed combination of light-sheet imaging in the larval zebrafish with visual stimulation and behavioral monitoring 20 enables simultaneous recording from virtually all neurons in the brain during sensorimotor behavior.”

“…to overcome tissue auto-fluorescence and successfully report single action potentials in live brain slices, at illumination intensities 500–1,000 times lower than those used for Arch (Gong et al., 146 Neuron 86, April 8, 2015 ª2015 Elsevier Inc. 2014; Hochbaum et al., 2014; St-Pierre et al., 2014).”

“Mice used their whiskers to navigate winding corridors in tactile virtual reality (Sofroniew et al., 2014).”

“The issue of temporally synchronized signals issue might be potentially addressed by recordings from multisensory areas [31] using a rodent in a virtual environment [34].”

“…norvegicus and Mus musculus have been found to reduce whisking 347 and protract their whisker forward, in a process called ‘look ahead’, which is thought to focus 348 the whiskers in front of the snout and prevent collisions with this sensitive area (Arkley et al. 349 2014; Sofroniew et al. 2014).”

“…whisking and aperture or gap crossing (Harris et al., 1999; Jenkinson and Glickstein, 2000; Crochet and Petersen, 2006; Celikel and Sakmann, 2007; Sofroniew et al., 2014; Kandler et al., 2018)—or paradigms embedded in an artificial task and require extensive training of the animal to interact…”

“Bending moment can permit wall following (Sofroniew et al. 2014) and, 274 if integrated across whiskers, can in principle be used both to infer object shape (Solomon 275 and Hartmann, 2006) and to map the spatial structure of the environment (Fox et al. 2012, 276 Pearson et al. 2013).”

“Whiskers are essential for wall-guided locomotion like the stimulus cylinder used here (Sofroniew et al., 2014).”

“However, virtual reality methods that provide tactile feedback are now also emerging (Sofroniew et al. 2014).”

“In complex sensory environments, whiskers are essential for them to gather information from surroundings as to guide their behaviors during exploration and navigation (Ahl, 1986; Diamond et al., 2008; Sofroniew et al., 2014; Yu et al., 2016).”

“Previous data, confirmed here (Figure S1), indicate a tight correlation between run-speed of themouse andwhisker set-point, which plateaus above 35 cm/s (Sofroniew et al., 2014).”

“Last, many groups have used head-fixed mice to perform complex memory and discrimination tasks (Dombeck et al., 2010; Komiyama et al., 2010; O’Connor et al., 2010; Chen et al., 2012; Sofroniew et al., 2014), in which the mice would not be able to perform if they were stressed by head fixation.”

“…in the sense that animals can control various parameters of whisking to suit a particular behavioral task (Carvell and Simons, 1995; Mitchinson et al., 2007; Hill et al., 2008; O’Connor et al., 2010a; Arkley et al., 2014; Maravall and Diamond, 2014; Sofroniew et al., 2014; Prescott et al., 2015).”

“In a treadmill system, navigation has been studied in mice directed by localized stimulations of their whiskers [17].”

“Virtual reality systems (Harvey et al. 2012; Saleem et al. 2018; Chen et al. 2018; Sofroniew et al. 2014) are commonly used for navigation tasks in head-fixed preparations, but have some significant drawbacks, such as a lack of depth cues, somatosensory feedback, and limited proprioceptive input.”

“5 s) placed near the center of the multiunit spatial receptive field, generating reproducible activity trial to trial (Sofroniew et al., 2014; Pluta et al., 2015, 2017).”

“Additionally, whisking can be triggered by sniffing, chewing, licking and walking (Welker 1964; Deschenes et al., 2012; Grant et al., 2012; Arkley et al., 2014; Sofroniew et al., 2014).”

“In a study of mouse locomotion and whisking movement, the maximum stride frequency attained by the mouse was 3 – 4 Hz, and the peak whisking frequency was 15 – 20 Hz (Sofroniew et al., 2014).”

“…relevant: exploring an object by whisker scanning or simply running along walls or tunnels will generate a series of fluctuations in whisker dynamics, concatenated over time (Wolfe et al., 2008; Jadhav et al., 2009; Jenks et al., 2010; Sofroniew et al., 2014; Sofroniew and Svoboda, 2015).”

“The radial distance of an object contacted 359 by the whiskers can be determined using ratios of different contact stresses (Pammer et al., 360 2013; Solomon and Hartmann, 2011).”

“In tactile VR systems for rodents, the animals move through corridors simulated by movable plates (Sofroniew et al., 2014) or rotating cylinders with different textures (Ayaz et al.”

“An alternative approach applied to the vibrissal sensory motor system has been to mount a tactile environment (a set of walls) that moves as the animal walks on an air ball (Sofroniew et al. 2014).”

“In a recent study, researchers placed two movable walls on either side of a mouse ’ s whiskers (Sofroniew et al., 2014).”

“A highly interesting emerging technique simulates body motion in head fixed mice using a virtual reality track ball system (Sofroniew et al. 2014).”

“Sequential transitions in texture may be encountered by mice running along walls or tunnels [33, 34] 360 and “receptive” sensation is also routinely mediated by whiskers [23].”

“Furthermore, continuous motor behaviours rely on ongoing sensory feedback (for example, stepping in rodents 47 or echolocation in bats 48 ), and both sensory and motor components are ideally suited to modulate neural activity.”

“In addition to object localisation, sensing of bending moment also accounts for wall-following behaviours (Sofroniew et al., 2014).”

“…speciesspecific, as are the number and distribution of vibrissae across the body’s surface (Pocock, 1914; Lyne, 1959; Ahl, 1982, 1986; Wineski, 1985; Sokolov and Kulikov, 1987; Marotte et al., 1992; 5 / Zoolo B g o t M S t c m d o c c k s r ( a m 2 m c w t l 1 e n l r e o a t 1 m n s f b b fi t t…”

“…mice have been trained to various tasks including bilateral-edge distance (Shuler et al., 2001; Krupa et al., 2004), gap width (Hutson & Masterton, 1986; Jenkinson & Glickstein, 2000), object localization (Knutsen et al., 2006), and virtual wall tracking behaviors (Sofroniew et al., 2014).”

“This is also a popular method for awake behavioral studies that trainmice to discriminate different textures while simultaneously performing electrophysiological recordings or optical imaging in vivo (O’Connor et al., 2010; Sofroniew et al., 2014; Kwon et al., 2016).”

“These back-and-forth sweeps or cycles result in the whiskers bending when they come into contact with an object or surface, which exerts forces on the follicle sinus at the base of each whisker (Sofroniew et al., 2014).”

“Limiting trainer contact also prevents biases in experimental outcome, which can arise, for example from differences in the animal ’ s reaction to male and female experimenters (Sorge et al., 2014).”

“These whiskers act as the ‘eyes’ of mouse especially in the dark [3] as these animals have evolved over time in a similar set of environments.”

“…functions, including the exploration of novel environments, object recognition, spatial navigation, prey capture, and social interactions (Anjum et. al, 2006; Brecht, 2007; Mitchinson et al., 2011; Feldmeyer et al., 2013; Bobrov et al., 2014; Sofroniew et al., 2014; Sofroniew and Svoboda, 2015).”

“Changes in L6 CT activity align better with whisking onset than locomotion but are more modulated during running Consistent with previous observations (Sofroniew et al., 2014; Ayaz et al., 2019), mice never walked/ran on the wheel without whisking.”

“…systems, and the movement of the platform is tracked in relation to a streaming visual or “real” world presented to the animal (Hölscher et al., 2005; Dombeck et al., 2007; Harvey et al., 2009; Sofroniew et al., 2014; Nashaat et al., 2017; Voigts and Harnett, 2018; Dominiak et al., 2019).”

“Virtual reality is increasingly being used for the presentation of vision-based navigational cues, but methods must be developed to extend these to affective and, above all, social behaviours, possibly with the inclusion of the controlled delivery of olfactory 146 and tactile cues 171 .”

“Here, we designed a task whereby mice run on a treadmill through a whisker-based tactile virtual reality system (inspired by Sofroniew et al. 42 and Ayaz et al. 43 ).”

“In addition, head-fixation is key to several behavioral paradigms that benefit from restricting the number of behavioral degrees of freedom [3].”

“In running rodents, whisking set points shift forward and whisking amplitudes decrease within the individual whisking bouts (Arkley et al., 2014; Sofroniew et al., 2014).”

“Very fast movements, however, like whisker movement 30,31 and pupil contraction 32,33 might not be fully detected using a 30 Hz configuration.”

“The bene!t of these systems is the tight control over the sensory experience of the animal, often during neural recordings (Maimon et al. 2010; Ahrens et al. 2012; Sofroniew et al. 2014).”

“These movements result in the whiskers bending when they come into contact with an object or surface, which exerts forces on the follicle sinus at the base of each whisker (Sofroniew et al ., 2014).”

“Based on the recorded running speed and measured whisker movements, we defined four different behavioral states (Figure 2A; Experimental Procedures): Animals spent about half of their time running, which was always accompanied by simultaneous whisking as reported previously (Sofroniew et al., 2014).”

“Mice use both vision and touch in virtual reality navigation behaviors (Sofroniew et al., 2014), yet it is not known how these senses are combined during exploratory behaviors.”

“Virtual reality setups have been developed to flexibly study neural activity during behavior [14–23].”

“Since running is strongly associated with natural whisking in awake mice (Sofroniew et al. 2014), we also quantified single-whisker movements in three mice using a deep-learning-based, marker-less pose estimation software (Mathis et al. 2018, Nath et al. 2019, Mathis et al. 2019).”

“[9] Rats Touch Rats use of whiskers to navigate in a virtual environment”

“Rodent whisking occurs around 8-16 Hz during active exploration 60,71,72 , which was found to be phase coupled to stepping in head-fixed mice 60 .”

“Next, we wanted to investigate if place cells remap in both VR and TM environments when mice are exposed to a novel context (Muller & Kubie 1987, Leutgeb et al. 2005).”

“As reported, we see whisking occurring at the same time as locomotion [37,38], where locomotion occurred PLOS COMPUTATIONAL BIOLOGY Data-driven segmentation of cortical calcium dynamics”

“…purely based on shape (Anjum et al., 2006)(Polley et al., 2005), and barrel cortex neurons are sensitive to the location (O’Connor et al., 2010)(Sofroniew et al., 2014)(Curtis and Kleinfeld, 2009), texture (Arabzadeh et al., 2003)(Isett et al., 2018)(Chen et al., 2013), shape (Anjum et al.,…”

“Since locomotion in mice and rats is tightly associated with natural whisking (Sofroniew et al., 2014), our locomotion behavioral state comprises both movement and whisking (Figure 1B).”

“Previous studies have reported that rodents actively move their whiskers to seek and identify objects or avoid obstacles in front of them during locomotion ( 42 – 45 ).”

“Therefore whisker-guided navigation in our VR is likely not learned, but rather a “spontaneous”(Oesch et al., 2024) or “naturalistic” (Sofroniew et al., 2014) behavior.”

“In our study, we discovered individual SC neurons that encoded both whisking and locomotion, hypothetically extending the role of the SC to the coordination of these coupled systems [44,45,68].”