State-dependent and cell type-specific temporal processing in auditory thalamocortical circuit

Ongoing spontaneous activity in cortical circuits defines cortical states, but it still remains unclear how cortical states shape sensory processing across cortical laminae and what type of response properties emerge in the cortex. Recording neural activity from the auditory cortex (AC) and medial geniculate body (MGB) simultaneously with electrical stimulations of the basal fore brain (BF) in urethane - anesthetized rats, we investigated state - dependent spontaneous and auditory-evoked activities in the auditory thalamocortical circuit. BF stimulation induced a short-lasting desynchronized state, with sparser firing and increased power at gamma frequency in superficial layers. In this desynchronized state, the reduction in onset response variability in both AC and MGB was accompanied by cell type-specific firing, with decreased responses of cortical broad spiking cells, but increased responses of cortical narrow spiking cells. This onset response was followed by distinct temporal evolution in AC, with quicker rebound firing in infragranular layers. This temporal profile was associated with improved processing of temporally structured stimuli across AC layers to varying degrees, but not in MGB. Thus, the reduction in response variability during the desynchronized state can be seen subcortically whereas the improvement of temporal tuning emerges across AC layers, emphasizing the importance of state - dependent intra cortical processing in hearing

Laminar-dependent effects of cortical state on auditory cortical spontaneous activity

Cortical circuits spontaneously generate coordinated activity even in the absence of external inputs. The character of this activity depends on cortical state. We investigated how state affects the organization of spontaneous activity across layers of rat auditory cortex in vivo, using juxtacellular recording of morphologically identified neurons and large-scale electrophysiological recordings. Superficial pyramidal cells (PCs) and putative fast-spiking interneurons (FSs) were consistently suppressed during cortical desynchronization. PCs in deep layers showed heterogeneous responses to desynchronization, with some cells showing increased rates, typically large tufted PCs of high baseline firing rate, but not FSs. Consistent results were found between desynchronization occurring spontaneously in unanesthetized animals, and desynchronization evoked by electrical stimulation of the pedunculopontine tegmental (PPT) nucleus under urethane anesthesia. We hypothesize that reduction in superficial layer firing may enhance the brain's extraction of behaviorally relevant signals from noisy brain activity

SaLSa : a combinatory approach of semi-automatic labeling and long short-term memory to classify behavioral syllables

Accurately and quantitatively describing mouse behavior is an important area. Although advances in machine learning have made it possible to track their behaviors accurately, reliable classification of behavioral sequences or syllables remains a challenge. In this study, we present a novel machine learning approach, called SaLSa (a combination of semi-automatic labeling and long short-term memory-based classification), to classify behavioral syllables of mice exploring an open field. This approach consists of two major steps: first, after tracking multiple body parts, spatial and temporal features of their egocentric coordinates are extracted. A fully automated unsupervised process identifies candidates for behavioral syllables, followed by manual labeling of behavioral syllables using a graphical user interface. Second, a long short-term memory (LSTM) classifier is trained with the labeled data. We found that the classification performance was marked over 97%. It provides a performance equivalent to a state-of-the-art model while classifying some of the syllables. We applied this approach to examine how hyperactivity in a mouse model of Alzheimer's disease (AD) develops with age. When the proportion of each behavioral syllable was compared between genotypes and sexes, we found that the characteristic hyper-locomotion of female AD mice emerges between 4 and 8 months. In contrast, age-related reduction in rearing is common regardless of genotype and sex. Overall, SaLSa enables detailed characterization of mouse behavior

Multisensory information facilitates reaction speed by enlarging activity difference between superior colliculus hemispheres in rats

Animals can make faster behavioral responses to multisensory stimuli than to unisensory stimuli. The superior colliculus (SC), which receives multiple inputs from different sensory modalities, is considered to be involved in the initiation of motor responses. However, the mechanism by which multisensory information facilitates motor responses is not yet understood. Here, we demonstrate that multisensory information modulates competition among SC neurons to elicit faster responses. We conducted multiunit recordings from the SC of rats performing a two-alternative spatial discrimination task using auditory and/or visual stimuli. We found that a large population of SC neurons showed direction-selective activity before the onset of movement in response to the stimuli irrespective of stimulation modality. Trial-by-trial correlation analysis showed that the premovement activity of many SC neurons increased with faster reaction speed for the contraversive movement, whereas the premovement activity of another population of neurons decreased with faster reaction speed for the ipsiversive movement. When visual and auditory stimuli were presented simultaneously, the premovement activity of a population of neurons for the contraversive movement was enhanced, whereas the premovement activity of another population of neurons for the ipsiversive movement was depressed. Unilateral inactivation of SC using muscimol prolonged reaction times of contraversive movements, but it shortened those of ipsiversive movements. These findings suggest that the difference in activity between the SC hemispheres regulates the reaction speed of motor responses, and multisensory information enlarges the activity difference resulting in faster responses

Fiber photometry-based investigation of brain function and dysfunction

Fiber photometry is an optical method to monitor fluorescent signals using a fiber optic cannula. Over the past two decades, together with the development of various genetically encoded biosensors, it has been applied to investigate various types of activity in the central nervous system. This includes not only type-specific neuronal population activity, but also non13 neuronal activity and neurotransmitter/neuropeptide signals in awake, freely behaving animals. In this perspective, we summarize the recent development of this technique. After describing common technical pitfalls, we discuss future directions of this powerful approach for investigating brain function and dysfunction

Pathway-dependent regulation of sleep dynamics in a network model of the sleep-wake cycle

Sleep is a fundamental homeostatic process within the animal kingdom. Although various brain areas and cell types are involved in the regulation of the sleep-wake cycle, it is still unclear how different pathways between neural populations contribute to its regulation. Here we address this issue by investigating the behavior of a simplified network model upon synaptic weight manipulations. Our model consists of three neural populations connected by excitatory and inhibitory synapses. Activity in each population is described by a firing-rate model, which determines the state of the network. Namely wakefulness, rapid eye movement (REM) sleep or non-REM (NREM) sleep. By systematically manipulating the synaptic weight of every pathway, we show that even this simplified model exhibits non-trivial behaviors: for example, the wake-promoting population contributes not just to the induction and maintenance of wakefulness, but also to sleep induction. Although a recurrent excitatory connection of the REM-promoting population is essential for REM sleep genesis, this recurrent connection does not necessarily contribute to the maintenance of REM sleep. The duration of NREM sleep can be shortened or extended by changes in the synaptic strength of the pathways from the NREM-promoting population. In some cases, there is an optimal range of synaptic strengths that affect a particular state, implying that the amount of manipulations, not just direction (i.e., activation or inactivation), needs to be taken into account. These results demonstrate pathway-dependent regulation of sleep dynamics and highlight the importance of systems-level quantitative approaches for sleep-wake regulatory circuits

State-dependent brainstem ensemble dynamics and their interactions with hippocampus across sleep states

The brainstem plays a crucial role in sleep-wake regulation. However, the ensemble dynamics underlying sleep regulation remain poorly understood. Here, we show slow, state-predictive brainstem ensemble dynamics and state-dependent interactions between the brainstem and the hippocampus in mice. On a timescale of seconds to minutes, brainstem populations can predict pupil dilation and vigilance states and exhibit longer prediction power than hippocampal CA1 neurons. On a timescale of sub-seconds, pontine waves (P-waves) are accompanied by synchronous firing of brainstem neurons during both rapid eye movement (REM) and non-REM (NREM) sleep. Crucially, P-waves functionally interact with CA1 activity in a state-dependent manner: during NREM sleep, hippocampal sharp wave-ripples (SWRs) precede P-waves. On the other hand, P-waves during REM sleep are phase-locked with ongoing theta oscillations and are followed by burst firing of CA1 neurons. This state-dependent global coordination between the brainstem and hippocampus implicates distinct functional roles of sleep

Cre-Dependent Optogenetic Transgenic Mice Without Early Age-Related Hearing Loss

With the advent of recent genetic technologies for mice, it is now feasible to investigate the circuit mechanisms of brain functions in an unprecedented manner. Although transgenic mice are commonly used on C57BL/6J (C57) background, hearing research has typically relied on different genetic backgrounds, such as CBA/Ca or CBA due to the genetic defect of C57 mice for early age-related hearing loss. This limits the utilization of available genetic resources for hearing research. Here we report congenic (>F10) Cre-dependent channelrhodopsin2 (ChR2) mice on CBA/Ca background. By crossing this line with Cre-driver mice on C57 background, F1 hybrids restored the hearing deficit of C57 mice. We also found a linear relationship between aging and hearing loss, with progression rates varied depending on genetic backgrounds (3.39 dB/month for C57; 0.82 dB/month for F1 hybrid). We further demonstrate that this approach allows to express ChR2 in a specific type of inhibitory neurons in the auditory cortex and that they can be identified within a simultaneously recorded population of neurons in awake mice. Thus, our Cre-dependent optogenetic transgenic mice on CBA/Ca background are a valuable tool to investigate the circuit mechanisms of hearing across lifespan

Simultaneous electrophysiology and fiber photometry in freely behaving mice

In vivo electrophysiology is the gold standard technique used to investigate sub-second neural dynamics in freely behaving animals. However, monitoring cell-type-specific population activity is not a trivial task. Over the last decade, fiber photometry based on genetically encoded calcium indicators (GECIs) has been widely adopted as a versatile tool to monitor cell-type-specific population activity in vivo. However, this approach suffers from low temporal resolution. Here, we combine these two approaches to monitor both sub-second field potentials and cell-type-specific population activity in freely behaving mice. By developing an economical custom-made system and constructing a hybrid implant of an electrode and a fiber optic cannula, we simultaneously monitor artifact-free mesopontine field potentials and calcium transients in cholinergic neurons across the sleep-wake cycle. We find that mesopontine cholinergic activity co-occurs with sub-second pontine waves, called P-waves, during rapid eye movement sleep. Given the simplicity of our approach, simultaneous electrophysiological recording and cell-type-specific imaging provides a novel and valuable tool for interrogating state-dependent neural circuit dynamics in vivo

Pre-prints : a more affordable and quicker way to share research results

The growing availability of a wide range of subject-based pre-print servers such as bioRxiv and ChemRxiv is driving the research funders' and institutions' policies towards promoting the deposit of early versions of research works in such platforms. This trend has only been reinforced by the emergence of the Covid-19 pandemic, which has reassured these key stakeholders that this is the right way forward in the domain of scholarly communications. Pre-prints not only allow a much earlier dissemination of research results, but they do not prevent the publication of the work in a well-respected journal following the standard peer-review process and they critically ensure the open availability of these usually publicly-funded research results at a very early stage. The talk will examine the workflows associated to pre-print deposit and later publication in a journal, the associated usage stats and citation advantages offered by these pre-print servers, the policies issued by specific research funders regarding pre-prints and the permissions offered by publishers for posting early, still unreviewed versions of a research work. A prominent Strathclyde researcher who regularly posts pre-prints on these servers will feature alongside the Open Access Advocacy Librarian to discuss these topics