Biology subjects

Sokoloff, G.

Publications and source records attributed to Sokoloff, G..

13 recordsLinked to original sources

bioRxiv2026

HOMEOSTATIC COUPLING OF CORTICAL AND BRAINSTEM DELTA RHYTHMS IN SLEEPING INFANT RATS

The emergence of the cortical delta rhythm (1-4 Hz) during quiet sleep (QS) is a major milestone in brain development. In rats, this milestone is achieved between 8 and 12 days of postnatal (P) age. We previously reported an age-dependent increase in PZ delta-rhythmic activity that is synchronized with cortical delta and entrained by breathing. Here, we ask whether this long-distance synchrony persists in response to perturbations to sleep homeostasis or respiration. First, using male and female P12 rats, we investigated the coupling strength between frontal cortex and PZ in response to a short but intense period of sleep deprivation. During recovery sleep, we observed a rebound in delta power in both PZ and cortex, even in the absence of increased QS duration, indicating that PZ and cortical delta power are equivalent markers of homeostatic sleep regulation. Analyses of phase-locking and lagged cross-correlation revealed persistent temporal coupling between the two rhythms such that cortical delta reliably lagged PZ delta regardless of changes in sleep pressure. Curiously, we also observed an increase in breathing depth during recovery sleep, which we confirmed in a separate cohort of pups. Next, using mild hypercapnia (5% CO2) to alter breathing frequency and depth, we produced decreases in cortical and PZ delta power along with decreases in the depth of breathing. These findings provide additional support for the notion that PZ and cortical delta rhythms function as distantly interconnected components within a developmentally emerging sleep-homeostatic system that is also intimately tied with the brainstem respiratory network. SIGNIFICANCE STATEMENTWe reported previously that the delta rhythm that defines slow-wave sleep is not confined to the forebrain but also occurs synchronously in the medulla. This study in infant rats uses two perturbations to assess the coupling strength of cortical and brainstem delta. Using sleep deprivation and hypercapnia, we show that delta power increases or decreases in lockstep in the two regions, respectively. Our results reinforce the notion that delta across these two regions is strongly coupled and adds a new dimension to our understanding of the interconnectedness of the delta rhythm and respiration.

neuroscience↗

bioRxiv2026

Twitching in sleeping premature infants provides a sensitive behavioral assay of early motor control

AO_SCPLOWBSTRACTC_SCPLOWLimb twitching is among the earliest observable behaviors in human development and a hallmark of active (REM) sleep. Systematic assessments in full-term infants have revealed functional features that informal observation cannot capture. Because preterm infants spend even more time asleep and are at heightened risk for neurodevelopmental disorders, we provide the first systematic characterization of twitching at 34-35 weeks postmenstrual age. Preterm infants exhibit an immense quantity of twitching across the body, underscoring its developmental significance. The spatiotemporal structure of twitching also changes with age, including a selective increase in finger and toe twitching. Unexpectedly, during periods of trace alternant, a precursor to quiet sleep, twitching appears in brief bouts that are almost exclusively restricted to the legs. These findings show how this abundant but overlooked sleep behavior provides a sensitive assay of the developing neural control of movement, with implications for understanding typical and atypical development.

animal behavior and cognition↗

bioRxiv2025

A transient feature of the inferior olive supports thedevelopment of cerebellar internal models

The inferior olive (IO) supports motor learning by supplying the cerebellum with critical sensory and motor input. In adult rats, that input includes externally generated limb stimulation. In contrast, the IO of postnatal day 8 (P8) rats does not exhibit responses to external stimuli. Instead, IO activity primarily reflects corollary discharges associated with the production of self-generated limb twitches during active (REM) sleep. Because corollary discharges are necessary for the computation of internal models, we tested the hypothesis that IO-related corollary discharge is necessary for the emergence of a functioning cerebellar internal model during development. First, by conducting extracellular recordings in the IO at P12 and P20, we confirmed the presence of twitch-related corollary discharge at both ages; however, whereas the IO at P20 responded to limb stimulation, the IO at P12 did not. Next, using a protocol for selectively lesioning the climbing fibers that connect the IO to the cerebellum, including the interpositus nucleus (IP), we confirmed that lesioning at P12 prevents the IPs expression of corollary discharge at P13. Finally, we assessed the necessity of IO input to the cerebellum for the emergence of an internal model by lesioning climbing fibers at P12 or P19 and testing for the expression of a cerebellar internal model in the thalamus at P20. Only when the lesions occurred at P12 was the expression of the internal model severely disrupted. These findings provide the most direct evidence to date linking twitch-related corollary discharge to the developmental emergence of a cerebellar-dependent internal model. SIGNIFICANCE STATEMENTIn adult animals, internal models of movement generated by the cerebellum are essential for smooth, precise, and adaptive behavior. It is known that these internal models must develop in early infancy in an experience-dependent fashion; however, it is not known how sensorimotor experience acting on the nascent cerebellar circuit gives rise to adult functions. Here, in pre-weanling rats, we show that self-generated signals during sleep provide the early experiences that shape cerebellar internal models. Our findings lay a foundation for understanding how neural activity during sleep shapes typical and atypical brain development.

neuroscience↗

bioRxiv2025

TWITCHES DURING N2 AND N3 ARE COUPLED WITH SLEEP SPINDLES BUT NOT DELTA OSCILLATIONS IN 6-MONTH-OLD INFANTS

Twitches are discrete movements that characterize REM sleep. However, recent work showed that twitches also occur during NREM sleep in human infants beginning around 3 months of age, a time when sleep spindles and the cortical delta rhythm are also emerging. Further, NREM twitches are coupled with sleep spindles, suggesting a unique contribution to sensorimotor development. Given that NREM sleep is composed of distinct substages, we investigated whether twitching and twitch-spindle coupling are differentially expressed during N2 and N3 sleep. In 6-month-old human infants (n=21; 7 females), we recorded EEG, respiration, and video during daytime sleep. We found high-intensity twitching during N2 and REM but not N3 sleep. In contrast, sleep spindles exhibited similar temporal characteristics during N2 and N3. Also, despite differences in the intensity of twitching during N2 and N3, significant twitch-spindle coupling occurred in both stages. Finally, the rate of twitching was inversely related to delta power across NREM periods. These findings suggest that although twitching occurs during REM, N2, and N3 sleep at this age, its expression is compatible with some sleep components (e.g., rapid eye movements, sleep spindles) but not others (e.g., cortical delta), highlighting the continuing need to better understand the dynamic organization of sleep and its individual components in early development. Statement of significanceTwitching has long been recognized as a core component of mammalian REM sleep. However, twitching also occurs during non-REM (NREM) sleep in human infants beginning around 3 months of age. Given that NREM sleep is composed of distinct stages (including N2 and N3), we asked whether the expression of twitching and its temporal coupling with sleep spindles is different between the two stages. Even though twitching was more intense during N2 than N3, twitch-spindle coupling occurred in both stages, again suggesting a unique and likely transient functional contribution to sensorimotor development. A necessary next step is to delineate the developmental trajectory of twitching and twitch-spindle coupling beyond 6 months of age.

neuroscience↗

bioRxiv2023

"Cortical Delta" In The Medulla Of Sleeping Infant Rats

In early development, active sleep is the predominant sleep state before it is supplanted by quiet sleep. In rats, the developmental increase in quiet sleep is accompanied by the sudden emergence of the cortical delta rhythm (0.5-4 Hz) around postnatal day 12 (P12). We sought to explain the emergence of cortical delta by assessing developmental changes in the activity of the parafacial zone (PZ), a medullary structure thought to regulate quiet sleep in adults. We recorded from PZ in P10 and P12 rats and predicted an age-related increase in neural activity during increasing periods of delta-rich cortical activity. Instead, during quiet sleep we discovered sleep-dependent rhythmic spiking activity--with intervening periods of total silence--phase-locked to a local delta rhythm. Moreover, PZ and cortical delta were coherent at P12, but not at P10. PZ delta was also phase-locked to respiration, suggesting sleep-dependent modulation of PZ activity by respiratory pacemakers in the ventral medulla. Disconnecting the main olfactory bulbs from the cortex did not diminish cortical delta, indicating that the influence of respiration on delta at this age is not mediated indirectly through nasal breathing. Finally, we observed an increase in parvalbumin-expressing terminals in PZ across these ages, supporting a role for GABAergic inhibition in PZs rhythmicity. The discovery of delta-rhythmic neural activity in the medulla--when cortical delta is also emerging--opens a new path to understanding the brainstems role in regulating sleep and synchronizing rhythmic activity throughout the brain.

neuroscience↗

bioRxiv2023

Developmentally unique cerebellar processing prioritizes self- over other-generated movements

AO_SCPLOWBSTRACTC_SCPLOWAnimals must distinguish the sensory consequences of self-generated movements (reafference) from those of other-generated movements (exafference). Only self- generated movements entail the production of motor copies (i.e., corollary discharges), which are compared with reafference in the cerebellum to compute predictive or internal models of movement. Internal models emerge gradually over the first three postnatal weeks in rats through a process that is not yet fully understood. Previously, we demonstrated in postnatal day (P) P8 and P12 rats that precerebellar nuclei convey corollary discharge and reafference to the cerebellum during active (REM) sleep when pups produce limb twitches. Here, recording from a deep cerebellar nucleus (interpositus, IP) in P12 rats of both sexes, we compared reafferent and exafferent responses to twitches and limb stimulations, respectively. As expected, most IP units showed robust responses to twitches. However, in contrast with other sensory structures throughout the brain, relatively few IP units showed exafferent responses. Upon finding that exafferent responses occurred in pups under urethane anesthesia, we hypothesized that urethane inhibits cerebellar cortical cells, thereby disinhibiting exafferent responses in IP. In support of this hypothesis, ablating cortical tissue dorsal to IP mimicked the effects of urethane on exafference. Finally, the results suggest that twitch-related corollary discharge and reafference are conveyed simultaneously and in parallel to cerebellar cortex and IP. Based on these results, we propose that twitches provide opportunities for the nascent cerebellum to integrate somatotopically organized corollary discharge and reafference, thereby enabling the development of closed-loop circuits and, subsequently, internal models. SO_SCPLOWIGNIFICANCEC_SCPLOW SO_SCPLOWTATEMENTC_SCPLOWFor adult animals to produce flexible and adaptive movements, they must distinguish self- from other-generated movements and learn to anticipate how their body moves through space. The computations required for this capacity occur within the cerebellar system. In early infancy, these computations are not yet established and must develop through sensorimotor experience. Here, we found that self-generated movements--particularly those movements occurring during active sleep--are a preferred source of that sensorimotor experience to the infant cerebellum. This preference appears to be unique to the infant cerebellum and helps us understand how that structure establishes its neural circuitry and functions.

neuroscience↗

bioRxiv2023

Cortical Representation of Movement Across the Developmental Transition to Continuous Neural Activity

Primary motor cortex (M1) exhibits a protracted period of development that includes the establishment of a somatosensory map long before motor outflow emerges. In rats, the sensory representation is established by postnatal day (P) 8 when cortical activity is still "discontinuous." Here, we ask how the representation survives the sudden transition to noisy "continuous" activity at P12. Using neural decoding to predict forelimb movements based solely on M1 activity, we show that a linear decoder is sufficient to predict limb movements at P8, but not at P12; in contrast, a nonlinear decoder effectively predicts limb movements at P12. The change in decoder performance at P12 reflects an increase in both the complexity and uniqueness of kinematic information available in M1. We next show that the representation at P12 is more susceptible to the deleterious effects of "lesioning" inputs and to "transplanting" M1s encoding scheme from one pup to another. We conclude that the emergence of continuous cortical activity signals the developmental onset in M1 of more complex, informationally sparse, and individualized sensory representations.

neuroscience↗

bioRxiv2021

Developmental onset of a cerebellar-dependent forward model of movement in motor thalamus

To execute complex behavior with temporal precision, adult animals use internal models to predict the sensory consequences of self-generated movement. Here, taking advantage of the unique kinematic features of twitches--the brief, discrete movements of active sleep--we captured the developmental onset of a cerebellar-dependent internal model. Using rats at postnatal days (P) 12, P16, and P20, we compared neural activity in two thalamic structures: the ventral posterior (VP) and ventral lateral (VL) nuclei, both of which receive somatosensory input but only the latter of which receives cerebellar input. At all ages, twitch-related activity in VP lagged behind movement, consistent with sensory processing; similar activity was observed in VL through P16. At P20, however, VL activity precisely mimicked the twitch itself, a pattern of activity that depended on cerebellar input. Altogether, these findings implicate twitches in the development and refinement of internal models of movement.

neuroscience↗

bioRxiv2021

Twitches emerge postnatally during quiet sleep in human infants and are synchronized with sleep spindles

SO_SCPLOWUMMARYC_SCPLOWIn humans and other mammals, the stillness of sleep is punctuated by bursts of rapid eye movements (REMs) and myoclonic twitches of the limbs [1]. Contrary to the notion that twitches are mere by-products of dreams, sensory feedback arising from twitching limbs provides a rich and unique source of activation to the developing sensorimotor system [2]. In fact, it is partly because of the behavioral activation of REM sleep that this state is also called active sleep (AS), in contrast with the behavioral quiescence that gives quiet sleep (QS)--the second major stage of sleep--its name. In human infants, for which AS occupies eight or more hours of each day [3], limb twitching is one among several components that help to identify the state [4-7]; nonetheless, we know relatively little about the structure and functions of twitching across development. Recently, in sleeping infants over the first seven postnatal months [8], we documented a pronounced shift in the temporal expression of twitching beginning around three months of age that suggested a qualitative shift in how twitches are produced. Here, we combine behavioral assessments of twitching with high-density electroencephalography (EEG) and demonstrate that this shift reflects the developmental emergence of limb twitches during QS. Twitches during QS are not only unaccompanied by REMs, but they also occur synchronously with sleep spindles, a hallmark of QS. As QS-related twitching increases with age, sleep spindle rate also increases along the sensorimotor strip. The emerging synchrony between subcortically generated twitches and cortical oscillations suggests the development of functional connectivity among distant sensorimotor structures, with potential implications for detecting and explaining atypical developmental trajectories.

neuroscience↗

bioRxiv2020

Sensory coding of limb kinematics in developing primary motor cortex

Primary motor cortex (M1) undergoes protracted development in mammals, functioning initially as a sensory structure. Throughout the first postnatal week in rats, M1 is strongly activated by self-generated forelimb movements--especially by the twitches that occur during active sleep. Here, we quantify the kinematic features of forelimb movements to reveal receptive-field properties of individual units within the forelimb region of M1. At postnatal day (P) 8, nearly all units were strongly modulated by movement amplitude, especially during active sleep. By P12, only a minority of units continued to exhibit amplitude-tuning, regardless of behavioral state. At both ages, movement direction also modulated M1 activity, though to a lesser extent. Finally, at P12, M1 population-level activity became more sparse and decorrelated, along with a substantial alteration in the statistical distribution of M1 responses to limb movements. These findings reveal a transition toward a more complex and informationally rich representation of movement long before M1 develops its motor functionality.

neuroscience↗

bioRxiv2020

Self-generated whisker movements drive state-dependent sensory input to developing barrel cortex

SO_SCPLOWUMMARYC_SCPLOWCortical development is an activity-dependent process [1-3]. Regarding the role of activity in developing somatosensory cortex, one persistent debate concerns the importance of sensory feedback from self-generated movements. Specifically, recent studies claim that cortical activity is generated intrinsically, independent of movement [3, 4]. However, other studies claim that behavioral state moderates the relationship between movement and cortical activity [5-7]. Thus, perhaps inattention to behavioral state leads to failures to detect movement-driven activity [8]. Here, we resolve this issue by associating local field activity (i.e., spindle bursts) and unit activity in the barrel cortex of 5-day-old rats with whisker movements during wake and myoclonic twitches of the whiskers during active (REM) sleep. Barrel activity increased significantly within 500 ms of whisker movements, especially after twitches. Also, higher-amplitude movements were more likely to trigger barrel activity; when we controlled for movement amplitude, barrel activity was again greater after a twitch than a wake movement. We then inverted the analysis to assess the likelihood that increases in barrel activity were preceded within 500 ms by whisker movements: At least 55% of barrel activity was attributable to sensory feedback from whisker movements. Finally, when periods with and without movement were compared, 70-75% of barrel activity was movement-related. These results confirm the importance of sensory feedback from movements in driving activity in sensorimotor cortex and underscore the necessity of monitoring sleep-wake states to ensure accurate assessments of the contributions of the sensory periphery to activity in developing somatosensory cortex.

neuroscience↗

bioRxiv2018

Genome-wide association study, replication, and mega-analysis using a dense marker panel in a multi-generational mouse advanced intercross line

Replication is considered to be critical for genome-wide association studies (GWAS) in humans, but is not routinely performed in model organisms. We explored replication using an advanced intercross line (AIL) which is the simplest possible multigenerational intercross. We re-genotyped a previously published cohort of LG/J x SM/J AIL mice (F34; n=428) using a denser marker set and also genotyped a novel cohort of AIL mice (F39-43; n=600) for the first time. We identified 110 significant loci in the F34 cohort, 36 of which were new discoveries attributable to the denser marker set; we also identified 27 novel significant loci in the F39-43 cohort. For traits measured in both cohorts (locomotor activity, body weight, and coat color), the genetic correlations were high, although, the F39-43 cohort showed systematically lower SNP-heritability estimates. We then attempted to replicate loci identified in either F34 or F39-43 in the other cohort. Albino coat color was robustly replicated; we observed only partial replication of associations for locomotor activity and body weight. Finally, we performed a mega-analysis of locomotor activity and body weight by combining F34 and F39-43 cohorts (n=1,028), which identified four novel loci. The incomplete replication was inconsistent with simulations we performed to estimate our power to replicate. This may reflect: 1) false positives errors in the discovery cohort, 2) environmental or genetic heterogeneity between the two samples, or 3) the systematic over estimation of the effect sizes at significant loci (\"Winners Curse\"). Our results demonstrate that it is difficult to replicate GWAS results even when using similarly sized discovery and replication cohorts drawn from the same population.

genetics↗

bioRxiv2018

Its not you, its me: Corollary discharge in precerebellar nuclei of sleeping infant rats

In week-old rats, somatosensory input arises predominantly from stimuli in the external environment or from sensory feedback associated with myoclonic twitches during active (REM) sleep. A previous study of neural activity in cerebellar cortex raised the possibility that the brainstem motor structures that produce twitches also send copies of motor commands (or corollary discharge, CD) to the cerebellum. Here, by recording from two precerebellar nuclei--the inferior olive and lateral reticular nucleus--we demonstrate that CD does indeed accompany the production of twitches. Within both structures, the CD signal comprises a surprisingly sharp activity peak within 10 ms of twitch onset. In the inferior olive, this sharp peak is attributable to the opening of slow potassium channels. We conclude that a diversity of neural activity is conveyed to the developing cerebellum preferentially during sleep-related twitching, enabling cerebellar processing of convergent input from CD and reafferent signals.

neuroscience↗