Journal of Neurophysiology

Forano, Marion; Franklin, David W.

doi: 10.1152/jn.00307.2023pmid: 38717332

Motor learning occurs through multiple mechanisms, including unsupervised, supervised (error-based) and reinforcement (reward-based) learning. Although studies have shown that reward leads to an overall better motor adaptation, the specific processes by which reward influences adaptation are still unclear. Here, we examine how the presence of reward affects dual-adaptation to novel dynamics, and distinguish its influence on implicit and explicit learning. Participants adapted to two opposing force fields in an adaptation/de-adaptation/error-clamp paradigm, where five levels of reward (a score and a digital face) were provided as participants reduced their lateral error. Both reward and control (no reward provided) groups simultaneously adapted to both opposing force fields, exhibiting a similar final level of adaptation, which was primarily implicit. Triple-rate models fit to the adaptation process found higher learning rates in the fast and slow processes, and a slightly increased fast retention rate for the reward group. While differences in the slow learning rate were only driven by implicit learning, the large difference in the fast learning rate was mainly explicit. Overall, we confirm previous work showing that reward increases learning rates, extending this to dual-adaptation experiments, and demonstrating that reward influences both implicit and explicit adaptation. Specifically, we show that reward acts primarily explicitly on the fast learning rate and implicitly on the slow learning rates.

Taylor, Chase E.; Mendenhall, Laura E.; Sunshine, Michael D.; Wilson, Jessica N.; Calulot, Chris M.; Sun, Ramon C.; Johnson, Lance A.; Alilain, Warren J.

doi: 10.1152/jn.00255.2023pmid: 38748407

The apolipoprotein (APOE) gene has been studied due to its influence on Alzheimer's disease (AD) development and work in an APOE mouse model recently demonstrated impaired respiratory motor plasticity following spinal cord injury (SCI). Individuals with AD often co-present with obstructive sleep apnea (OSA) characterized by cessations in breathing during sleep. Despite the prominence of APOE genotype and sex as factors in AD progression, little is known about the impact of these variables on respiratory control. Ventilation is tightly regulated across many systems, with respiratory rhythm formation occurring in the brainstem but modulated in response to chemoreception. Alterations within these modulatory systems may result in disruptions of appropriate respiratory control and ultimately, disease. Using mice expressing two different humanized APOE alleles, we characterized how sex and the presence of APOE3 or APOE4 influences ventilation during baseline breathing (normoxia) and during respiratory challenge. We show that sex and APOE genotype influence breathing during hypoxic challenge, which may have clinical implications in the context of AD and OSA. Additionally, female mice, while responding robustly to hypoxia, were unable to recover to baseline respiratory levels, emphasizing sex differences in disordered breathing.

Kaneko, Megumi; Hoseini, Mahmood S.; Waschek, James A.; Stryker, Michael P.

doi: 10.1152/jn.00463.2023pmid: 38774975

When adult mice are repeatedly exposed to a particular visual stimulus for as little as one hour per day for several days while their visual cortex (V1) is in the high-gain state produced by locomotion, that specific stimulus elicits much stronger responses in V1 neurons for the following several weeks, even when measured in anesthetized animals. Such stimulus-specific enhancement (SSE) is not seen if locomotion is prevented. The effect of locomotion on cortical responses is mediated by vasoactive intestinal peptide (VIP) positive interneurons, which can release both the peptide and the inhibitory neurotransmitter GABA. Previous studies have examined the role of VIP-ergic interneurons, but none have distinguished the individual roles of peptide from GABA release. Here we used genetic ablation to determine which of those molecules secreted by VIP-ergic neurons is responsible for SSE. SSE was not impaired by VIP deletion but was prevented by compromising release of GABA from VIP cells. This finding suggests that SSE may result from Hebbian mechanisms that remain present in adult V1.

Brockett, Adam T.; Francis, Nikolas A.

doi: 10.1152/jn.00124.2024pmid: 38810366

Psilocybin is a serotonergic psychedelic believed to have therapeutic potential for neuropsychiatric conditions. Despite well-documented prevalence of perceptual alterations, hallucinations, and synesthesia associated with psychedelic experiences, little is known about how psilocybin affects sensory cortex or alters the activity of neurons in awake animals. To investigate, we conducted 2-photon imaging experiments in auditory cortex of awake mice and collected video of free-roaming mouse behavior, both at baseline and during psilocybin treatment. In comparison with pre-dose neural activity, a 2 mg/kg intraperitoneal dose of psilocybin initially increased the amplitude of neural responses to sound. 30 minutes post-dose, behavioral activity and neural response amplitudes decreased, yet functional connectivity increased. In contrast, control mice given intraperitoneal saline injections showed no significant changes in either neural or behavioral activity across conditions. Notably, neuronal stimulus selectivity remained stable during psilocybin treatment, for both tonotopic cortical maps and single-cell pure-tone frequency tuning curves. Our results mirror similar findings regarding the effects of serotonergic psychedelics in visual cortex and suggest that psilocybin modulates the balance of intrinsic versus stimulus-driven influences on neural activity in auditory cortex.

Cicero, Nicholas G.; Klimova, Michaela; Lewis, Laura D.; Ling, Sam

doi: 10.1152/jn.00073.2024pmid: 38810261

Closing our eyes largely shuts down our ability to see. That said, our eyelids still pass some light, allowing our visual system to coarsely process information about visual scenes, such as changes in luminance. However, the specific impact of eye closure on processing within the early visual system remains largely unknown. To understand how visual processing is modulated when eyes are shut, we used functional magnetic resonance imaging (fMRI) to measure responses to a flickering visual stimulus at high (100%) and low (10%) temporal contrasts, while participants viewed the stimuli with their eyes open or closed. Interestingly, we discovered that eye closure produced a qualitatively distinct pattern of effects across the visual thalamus and visual cortex. We found that with eyes open, low temporal contrast stimuli produced smaller responses, across the lateral geniculate nucleus (LGN), primary (V1) and extrastriate visual cortex (V2). However, with eyes closed, we discovered that the LGN and V1 maintained similar BOLD responses as the eyes open condition, despite the suppressed visual input through the eyelid. In contrast, V2 and V3 had strongly attenuated BOLD response when eyes were closed, regardless of temporal contrast. Our findings reveal a qualitatively distinct pattern of visual processing when the eyes are closed - one that is not simply an overall attenuation, but rather reflects distinct responses across visual thalamocortical networks, wherein the earliest stages of processing preserves information about stimuli but is then gated off downstream in visual cortex.

Zimmermann, Eckart

doi: 10.1152/jn.00117.2024pmid: 38810256

Temporal intervals appear compressed at the time of saccades. Here, I asked if saccadic compression of time is related to motor planning or to saccade execution. To dissociate saccade motor planning from its execution, I used the double-step paradigm, in which subjects have to perform two horizontal saccades successively. At various times around the saccade sequence, I presented two large horizontal bars, which marked an interval lasting 100 ms. After 1000 ms, a second temporal interval was presented, varying in duration across trials, and subjects were required to judge which interval appeared shorter. I found that during the first saccades in the double-step paradigm, temporal intervals were compressed. Maximum temporal compression coincided with saccade onset. Around the time of the second saccade, I found temporal compression as well, however, the time of maximum compression occurred 70 ms before saccade onset. I compared the magnitude and time of temporal compression between double-step saccades and amplitude-matched single saccades, which I measured separately. While I found no difference in time compression magnitude, the time when maximum compression occurred differed significantly. I conclude that the temporal shift of time compression in double-step saccades demonstrates the influence of saccade motor planning on time perception.

Saito, Yasuhiko; Sugimura, Taketoshi

doi: 10.1152/jn.00019.2024pmid: 38838298

The prepositus hypoglossi nucleus (PHN) and the interstitial nucleus of Cajal (INC) are involved in the control of horizontal and vertical gaze, respectively. A previous study showed that PHN neurons exhibit depolarized or hyperpolarized responses to noradrenaline (NA). However, the adrenoceptor types that participate in NA-induced responses and the effects of NA on INC neurons have not yet been investigated. Furthermore, the relationship between NA-induced responses and neuron types defined by neurotransmitter phenotypes has not been determined. In this study, we investigated NA-induced current responses in PHN and INC neurons and the relationships between these responses and neuron types using whole-cell recordings in wild-type and transgenic rat brainstem slices. Local application of NA to the cell soma induced slow inward (SI) and slow outward (SO) currents that were mainly mediated by α1 and α2 adrenoceptors, respectively. These current responses were observed in both PHN and INC neurons, although the proportion of INC neurons that responded to NA was low. Analyses of the distributions of the current responses revealed that in the PHN, all fluorescently identified inhibitory neurons exhibited SI currents, whereas glutamatergic and cholinergic neurons exhibited both SI and SO currents. In the INC, glutamatergic and inhibitory neurons preferentially exhibited SI and SO currents, respectively. When the PHN and INC neurons were characterized by their firing pattern, we found that the proportions of the currents depended on their firing pattern. These results suggest that various modes of noradrenergic modulation in horizontal and vertical neural integrators are dependent on neuron type.

Kim, Dongwon; Ko, Sung-Hwa; Han, Junhee; Kim, Young-Taek; Kim, Yun-Hee; Chang, Won Hyuk; Shin, Yong-Il

doi: 10.1152/jn.00067.2024pmid: 38691520

Stroke-caused synergies may result from preferential use of the reticulospinal tract (RST) due to damage to the corticospinal tract. The RST branches multiple motoneuron pools across the arm together resulting in gross motor control or muscle synergies, and accordingly the controllability of individual muscles is reduced. It is not clear whether the muscles involuntarily activated by abnormal synergy vary with the muscles voluntarily activated when motor commands descend through the RST. Studies showed that abnormal synergies may originate from merging and re-weighting of synergies individuals without neurological deficit. This leads to a hypothesis that those abnormal synergies are still selectively excited depending on the context. In this study, we test this hypothesis, leveraging the Fugl-Meyer assessment (FMA) that could characterize the neuroanatomical architecture in individuals with a wide range of impairment. We examine the ability to perform an out-of-synergy movement with the flexion synergy caused by either shoulder or elbow loading. The results reveal that about 14% (8/57, 95%CI: [5.0%, 23.1%]) of the participants with severe impairment (total FM score <29) in the chronic phase (6 months after stroke) are able to keep the elbow extended during shoulder loading and keep the shoulder at neutral during elbow loading. Those participants undergo a different course of neural reorganization which enhanced abnormal synergies in comparison with individuals with mild impairment (p<0.05). These results evidence that separate routes and synergy modules to motoneuron pools across the arm might exist even if the motor command is mediated possibly via the RST.

Kim, Dongwon; Ko, Sung-Hwa; Han, Junhee; Kim, Young-Taek; Kim, Yun-Hee; Chang, Won Hyuk; Shin, Yong-Il

doi: 10.1152/jn.00102.2024pmid: 38748436

Background and Objectives: The flexion synergy and extension synergy are a representative consequence of a stroke and appear in the upper extremity and lower extremity. Since the ipsilesional corticospinal tract (CST) is the most influential neural pathway for both extremities in motor execution, damage by a stroke to this tract could lead to similar motor pathological features (e.g., abnormal synergies) in both extremities. However, less attention has been paid to the inter-limb correlations in the flexion synergy and extension synergy across different recovery phases of a stroke. Methods: We used results of the Fugl-Meyer assessment (FMA) to characterize those correlations in a total of 512 participants with hemiparesis post stroke from the acute phase to 1 year. The FMA provides indirect indicators of the degrees of the flexion synergy and extension synergy post stroke. Results: We found that generally, strong inter-limb correlations (r>0.65 with all p-values<0.0001) between the flexion synergy and extension synergy appeared in the acute-to-subacute phase (<90 days). But correlations of lower-extremity extension synergy with upper-extremity flexion synergy and extension synergy decreased (down to r=0.38) around 360 days after stroke (p<0.05). Discussion: These results suggest that preferential use of alternative neural pathways after damage by a stroke to the CST enhances inter-limb correlations between the flexion synergy and extension but a recovery of the CST functional and the fragmentation (remodeling) of the alternative neural substrates in the chronic phase contribute to diversity in neural pathways in motor execution, eventually leading to reduced inter-limb correlations.

Hill, Evan S.; Wang, Jean; Brown, Jeffrey W.; Mistry, Viral K.; Frost, William N.

doi: 10.1152/jn.00001.2024pmid: 38777746

In response to a suitably aversive skin stimulus, the marine mollusk Tritonia diomedea launches an escape swim followed by several minutes of high-speed crawling. The two escape behaviors are highly dissimilar: whereas the swim is a muscular behavior involving alternating ventral and dorsal whole-body flexions, the crawl is a non-rhythmic gliding behavior mediated by the beating of foot cilia. The serotonergic dorsal swim interneurons (DSIs) are members of the swim CPG and also strongly drive crawling. While the swim network is very well understood, the Tritonia crawling network to date comprises only three neurons: the DSIs, and pedal neurons 5 and 21 (Pd5 and Pd21). Since Tritonia's swim network has been suggested to have arisen from a pre-existing crawling network, we examined the possible role that another swim CPG neuron, C2, may play in crawling. Due to its complete silence in the post-swim crawling period, C2 had not previously been considered to play a role in driving crawling. However, semi-intact preparation experiments demonstrated that a brief C2 spike train surprisingly and strongly drives the foot cilia for ~30 s, something which cannot be explained by its synaptic connections to Pd5 and Pd21. Voltage-sensitive dye (VSD) imaging in the pedal ganglion identified many candidate crawling motor neurons that fire at an elevated rate following the swim, and also revealed several pedal neurons that are strongly excited by C2. It is intriguing that unlike the DSIs, which fire tonically after the swim to drive crawling, C2 does so despite its post-swim silence.