Flow of Cortical Activity Underlying a Tactile Decision in Mice

“Genetic tools in mice enable temporally precise circuit manipulations (Guo et al., 2014), but forelimb kinematics have not been analyzed to extract primitives as in Figure 1, in part because trajectory segmentation requires sensitivity to resolve the rapid, tiny details of motion that occur at…”

“Many studies using animal stroke models have confirmed this significant increase in NSE (Horn et al., 1995; Yi et al., 2008; Gelderblom et al., 2013; Guo et al., 2014).”

“For instance, in mice trained in a memory-guided directional licking task, a large proportion of ALM neurons were selective for licking direction (left/right) before and during licking 11,31,13–15 .”

“After head-plating, Metabond dental acrylic was thinned, smoothed, and cleaned to increase the transparency of the skull for optogenetic silencing (Guo et al., 2014; Hira et al., 2009).”

“…grooming behavior, suggesting LOFC serves to inhibit abnormal behavior generated in CS. 23 However, CS inputs from ALM, a region associated with (1) tongue movements important for grooming and (2) preparation, sustainment, and sequencing of trained behavior, 19,20,24–27 have not yet been examined.”

“categorization, we employed optogenetics to inactivate PPC in a more temporally controlled fashion (25).”

“Several papers from the laboratory of Karel Svoboda investigated temporal relationships between separate brain areas by employing optogenetic tools (O’Connor et al., 2013; Guo et al., 2014).”

“In rodents, the primary somatosensory cortex is required for whisker-based tactile sensation of objects in the surrounding (Guo et al., 2014; Petersen, 2014).”

“For wide fi eld imaging, 2Niell/J mice were similarly prepared, but a skull clearing procedure was performed instead of the cranial window 92 : the skull was thoroughly cleaned and covered with a thin, transparent layer of cyanoacrylate (Zap-A-Gap CA +, Pacer technology) to obtain optical access to…”

“Targeted photostimulation would activate PV interneurons in the left or right ACAd/MOs ( Figure 6B ), which would in turn silence local excitatory spiking activity ( Guo et al. 2014 ; Li et al. 2019).”

“…2012; Harvey et al., 2012; Glickfeld et al., 2013; Lee et al., 2013; Olcese et al., 2013; Zagha et al., 2013; Fu et al., 2014; Zhang et al., 2014; Guo et al., 2014a; Li et al., 2015; Kim et al., 2016; Kwon et al., 2016; Burgess et al., 2017; Licata et al., 2017; Mohan et al., 2018; Pho et al.,…”

“In normal mice (without any ischemic injury), inactivation of ALM neurons altered tactile decision-making behaviors, suggesting that neuronal activity in the ALM is related to preparatory activity and peri-movement and can be modulated by optogenetic silencing (Guo et al., 2014).”

“This temporal precision has also enabled localization of motor cortical influence to specific behavioral phases in decisionmaking paradigms (Guo et al., 2013; Goard et al., 2016), and to kinematically distinct movement features that likely have a distinct dependence on sensory feedback (Bollu et al.”

“The proportion of units classified as wide waveform and narrow waveform was in line with previously observed proportions 13,44 .”

“For our analysis, we focus on 8 brain areas, 6 highly relevant to the task [19, 29, 18, 49, 9] and 2 orbital areas: ALM, lOrb, vlOrb, Pallidum, Striatum, VAL-VM, MRN, and SC (see Appendix A.1 for full area names).”

“Head-fi xed preparations are widely used in neuroscience research, providing optical access to the brain for cellular calcium imaging 4 and optogenetic stimulation 5 as well as the ability to present controlled stimuli to animals 6,7 .”

“In complementary experiments, we optogenetically inhibited S1 via excitation of GABAergic neurons 12,27 in PV-Cre;Ai32 mice (Figure 7).”

“32,55 However, a direct causal relationship between persistent activity in sensory cortices and the encoding of working memory has been elusive.”

“Extracting behaviorally-relevant environmental state information (and keeping it in working memory) likely involves cortical processing 66,77–79 , and our results suggest that motor cortex is an essential conduit for conveying this information to subcortical motor circuits.”

“, 2017) from multiple brain areas of mice performing a delayed-response task (Figure 2A; Guo et al., 2014; Chen et al., 2023).”

“ALM is implicated in holding the short-term memory of future action (29, 30, 32, 37, 43) and tongue movements (31).”

“Because our controls were C57BL/6 mice [31] (injected with AAV-hSyn-eGFP), we also included in the experimental group some C57BL/6 mice (injected with AAV-CaMKIIα-GtACR2 to express the inhibitory opsin in excitatory neurons).”

“In rodents, sensorimotor coordination has been investigated using a number of behavioral tasks (Siegel et al., 2012; Guo et al., 2014; Murakami et al., 2014; Goard et al., 2016).”

“While it is likely that some inhi-bitoryinterneuronshadwiderwaveformsthanthisthreshold,previous results using optical tagging to identify GABAergic neurons suggest that the fraction of wide-waveform neurons that are GABAergic is very low 35,117 .”

“We next deployed a well-established mouse behavioral paradigm, delayed two-alternative forced choice (d2AFC), which was used to study motor planning in mouse Guo et al., 2014b ; Inagaki et al., 2018 , in HABITS to demonstrate the performance of our system ( Figure 2 ).”

“…first recording session (post-session #1), probes will be located in V1 and in cortical areas receiving direct monosynaptic projections from V1 such as HVAs, the premotor region ALM [53] – an area that receives strong projections from dorsomedial HVAs [54] – and the anterior cingulate cortex (ACC).”

“To test this, we bilaterally inhibited the different cortical areas shortly before stimulus onset via optogenetic activation of parvalbumin-positive (PV) GABAergic neurons 18,49 (Fig.”

“Complicated tasks often require long training programs (Guo et al., 2014; Harvey et al., 2012), which yields a considerable amount of behavioral data.”

“This work was predated by the understanding that a particular brain area known as anterior lateral motor (ALM) cortex is a key node in short-term memory representations of action preparation in mice (Guo et al., 2014).”

“54 To activate the direct or indirect pathway, we injected D1-cre (x Thy1-GCaMP6f) and D2-cre (x Thy1-GCaMP6f) mice with AAV5-syn -Flex- rcChrimsonR-tdTomato or AAV1-EF1a-DIO-hChR2-eYFP in the ventromedial part of the dorsal striatum of the right hemisphere (hemisphere Opto , Figure 1).”

“It is well established that preparatory activity in a variety of brain regions can reflect decisions regarding when or where to move 31,38-42 .”

“To identify cortical regions involved in task performance, we used an unbiased optogenetic inactivation approach ( Guo et al., 2014 ) using a 1- mm-spaced grid of target locations covering the left hemisphere of the mouse brain.”

“High variability in limb trajectories is critical to estimating the true dimensionality of somatosensation, as dimensionality is reduced during highly stereotyped movements [56].”

“…a delay period between the stimulus and the behavioral output that examined the activity in sensory regions, have uncovered enhanced or suppressed neuronal activity in primary sensory areas of expert mice, such as the visual cortex (Goard et al, 2016) and the barrel cortex (Guo et al, 2014).”

“In parallel, the same characteristics of mice (transparent skulls and transgenic suitability) have enabled the application of optogenetics across cortical areas (Guo et al., 2014; Pinto et al., 2019; Zatka-Haas et al., 2021).”

“Go/No-Go tasks, which are widely employed behavioral paradigms, are particularly vulnerable to choice biases owing to differences in motivational level, task engagement (attention), and reward expectations between choice options 7–9 .”

“…the higher order motor area such as M2 (Ueta et al. 2014; Hasegawa et al. 2020), which is responsible for goal-directed behavior and motor planning (Guo et al. 2014; Li et al. 2015; Allen et al. 2017), and its neuronal ensemble activity can be modified by motor learning (Cao et al. 2015; Makino et…”

“Research in invertebrates (Briggman et al., 2005; Kato et al., 2015), rodents (Hanks et al., 2015; Guo et al., 2014), monkeys (Roitman and Shadlen, 2002; Churchland et al., 2008), and humans (Pereira et al., 2021; Kelly and O’Connell, 2013) has attempted to understand the neural basis for…”

“For example, as mice move from preparing for a motor task to actual movement, neuronal activity travels from confinement within ALM to superficial ALM layers and finally to other motor cortical regions (Chen et al., 2017).”

“We observed that the optogenetic inactivation of 1PCFA neurons during the 1-2P period by photostimulation of Channelrhodopsin 2 (ChR2) expressed in cortical inhibitory interneurons (Zhao et al., 2011; Guo et al., 2014) also significantly reduced the biPress task performance (Extended Data Fig.”

“Understanding how brain information processing is implemented during cognitive tasks requires the interpretation of neuronal activities at multiple scales (Romo and De Lafuente, 2013; Guo et al., 2014).”

“The successive network links from the primary sensory regions is consistent with observations of serial information flow from barrel field sensory to motor areas in a tactile decision task in mice [63].”

“…range of cortical areas through inactivation, have revealed inactivation of two cortical regions to be effective in blocking task performance: 1) the primary sensory cortex (e.g. somatosensory) involved in detection; 2) premotor (ALM/M2) cortex (Allen et al. 2017; Guo et al. 2014; Li et al. 2016).”

“In Vivo Data The algorithm and the Matlab function were also tested with two publicly available recordings, one from mouse cortex in vivo [11,12] (for the experiment description see also [13]), and one from a slice of the freshly-resected human temporal cortex2 surgically removed to treat complex partial seizures (see…”

“There are certain questions that can only be answered by physiologic experimentation in a living animal: mapping neuronal circuitry to behavior (12) and regulation of vascular tone (13), to name two.”

“Perception is a complex, 1118 Neuron 86, June 3, 2015 ª2015 Elsevie highly integrative and adaptive cognitive function, and we are only just beginning to define the underlying long-range circuitry (Xu et al., 2012; Yamashita et al., 2013; Guo et al., 2014; Zhang et al., 2014).”

“Initial training and task structure were similar to previous studies ( Guo et al., 2014a ; Guo et al., 2014b ; Inagaki et al., 2018 ) and shown in Figure 1A.”

“…1986; Krupa et al., 1999; Krupa et al., 2001; von Heimendahl et al., 2007; O'Connor et al., 2010; Miyashita and Feldman, 2012; Feldmeyer et al., 2013; Guo et al., 2014a; Burgess et al., 2017; Fassihi et al., 2017; Chakrabarti and Schwarz, 2018; Hong et al., 2018; Odoemene et al., 2018;…”

“Similar to other delayed-response 2-AC tasks commonly used to study sensorimotor planning in ALM ( 6 – 9 ), a delay period (3 s) separates taste sampling and lateral lick decisions.”

“Time-resolved optogenetic inhibition of the BFD response has been previously demonstrated by activation of GABAergic circuits [5,40].”

“This indicated that data-constrained large-scale models are well-suited to explore decision-related information pathways in cortical networks, and to uncover the mechanisms behind sequential decision stages (Finkelstein et al., 2021; Guo et al., 2014).”

“A way of reconciling these findings could be that layer 2/3 neurons perform a variety of independent functions, such as motor preparation, outcome processing and working memory 33,34,44 .”

“In a previous study, head-fixation was found to be aversive, but with training and habituation, stress re-cedes (Z.V. Guo et al., 2014), and rodents can even be trained to restrain themselves (Murphy et al., 2020; Scott et al., 2013; Aoki et al., 2017).”

“Optical fiber implants and optogenetic experiments VGAT-ChR2-EYFP mice (Zhao et al., 2011; Guo et al., 2014) were chronically implanted with fiber implants to shine light on the surface of the barrel cortex (BCx) during TTEBC.”

“Second, in the somatosensory cortex, a region that is required to localize objects with vibrissae (O’Connor et al., 2010; Guo et al., 2014), there is a continuous transformation of sensory and efference copy signals along sensorimotor loops (Kleinfeld et al.”

“ALM is involved in motor planning of directional licking (Guo et al., 2014a; Li et al., 2015; Bollu et al., 2021; Xu et al., 2022) whereas RFA is thought to be involved in motor planning of forelimb movement (Hasegawa et al., 2017; Morandell and Huber, 2017).”

“8 guidance from wide-field calcium imaging (Figures 2 and S2), optical intrinsic imaging and previous literature (Esmaeili and Diamond, 2019; Guo et al., 2014; Harvey et al., 2012; Kyriakatos et al., 2017; Le Merre et al., 2018; Mayrhofer et al., 2019; Sippy et al., 2015; Sreenivasan et al., 2016): visual (Vis), whisk…”

“To study active tactile processing, we trained head-restrained mice to use a subset of 1-3 whiskers to scan space for an object (pole) and report the result by licking (Guo et al., 2014a; Hires et al., 2015; O’Connor et al., 2010a, 2013; Yu et al., 2016).”