Non-motor symptoms associated with progressive loss of dopaminergic neurons in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is characterized by three main motor symptoms: bradykinesia, rigidity and tremor. PD is also associated with diverse non-motor symptoms that may develop in parallel or precede motor dysfunctions, ranging from autonomic system dysfunctions and impaired sensory perception to cognitive deficits and depression. Here, we examine the role of the progressive loss of dopaminergic transmission in behaviors related to the non-motor symptoms of PD in a mouse model of the disease (the TIF-IADATCreERT2 strain). We found that in the period from 5 to 12 weeks after the induction of a gradual loss of dopaminergic neurons, mild motor symptoms became detectable, including changes in the distance between paws while standing as well as the swing speed and step sequence. Male mutant mice showed no apparent changes in olfactory acuity, no anhedonia-like behaviors, and normal learning in an instrumental task; however, a pronounced increase in the number of operant responses performed was noted. Similarly, female mice with progressive dopaminergic neuron degeneration showed normal learning in the probabilistic reversal learning task and no loss of sweet-taste preference, but again, a robustly higher number of choices were performed in the task. In both males and females, the higher number of instrumental responses did not affect the accuracy or the fraction of rewarded responses. Taken together, these data reveal discrete, dopamine-dependent non-motor symptoms that emerge in the early stages of dopaminergic neuron degeneration.

Local contribution to the somatosensory evoked potentials in rat's thalamus.

Local Field Potential (LFP), despite its name, often reflects remote activity. Depending on the orientation and synchrony of their sources, both oscillations and more complex waves may passively spread in brain tissue over long distances and be falsely interpreted as local activity at such distant recording sites. Here we show that the whisker-evoked potentials in the thalamic nuclei are of local origin up to around 6 ms post stimulus, but the later (7-15 ms) wave is overshadowed by a negative component reaching from cortex. This component can be analytically removed and local thalamic LFP can be recovered reliably using Current Source Density analysis. We used model-based kernel CSD (kCSD) method which allowed us to study the contribution of local and distant currents to LFP from rat thalamic nuclei and barrel cortex recorded with multiple, non-linear and non-regular multichannel probes. Importantly, we verified that concurrent recordings from the cortex are not essential for reliable thalamic CSD estimation. The proposed framework can be used to analyze LFP from other brain areas and has consequences for general LFP interpretation and analysis.

kCSD-python, reliable current source density estimation with quality control.

Interpretation of extracellular recordings can be challenging due to the long range of electric field. This challenge can be mitigated by estimating the current source density (CSD). Here we introduce kCSD-python, an open Python package implementing Kernel Current Source Density (kCSD) method and related tools to facilitate CSD analysis of experimental data and the interpretation of results. We show how to counter the limitations imposed by noise and assumptions in the method itself. kCSD-python allows CSD estimation for an arbitrary distribution of electrodes in 1D, 2D, and 3D, assuming distributions of sources in tissue, a slice, or in a single cell, and includes a range of diagnostic aids. We demonstrate its features in a Jupyter Notebook tutorial which illustrates a typical analytical workflow and main functionalities useful in validating analysis results.

Reappraisal of intradural findings in Chiari malformation type I.

OBJECTIVE: Management of Chiari malformation type I (CM-I) requires the functional restoration of an obstructed cisterna magna. In posterior fossa decompression with duraplasty (PFDD), various intradural pathologies are suggested to alter CSF flow at the craniocervical junction and require surgical correction. However, reports of the spectrum of intraoperative intradural findings and their nuances are scarce, especially those characterizing rarer findings pertaining to the vascular structures and vascular compression. METHODS: The authors conducted a retrospective cohort analysis of adults and children who underwent first-time PFDD for CM-I (2011-2021), with and without syringomyelia. The surgical reports and intraoperative videos were reviewed, and the frequency and nature of the intradural observations in regard to the tonsils, arachnoid, and vasculature were analyzed along with the clinical findings and surgical outcomes. RESULTS: All 180 patients (age range 1-72 years; median [interquartile range] 24 (14-38) years; 37% of patients were children < 21 years of age) exhibited multiple intradural findings, with a median of 7 distinct concurrent observations in each patient. Novel findings not previously reported included posterior inferior communicating artery (PICA) branches compressing the neural elements at the cervicomedullary junction (26.7%). Other common findings included arachnoid adhesions (92.8%), thickening (90.6%), webs at the obex (52.2%), tonsillar gliosis (57.2%), tonsillar hypertrophy (18.3%), adhesions obstructing the foramen of Magendie (FoM) (62.2%), PICA obstruction of the FoM (17.2%), and dural scarring (87.8%). Tonsillar gliosis and intertonsillar adhesions obstructing the FoM were more common in children than adults. Tonsillar gliosis and arachnoid webs were more common among syringomyelia patients. After multivariable adjustment, none of the observed findings were independently associated with syringomyelia, preoperative symptoms, or postoperative improvement. The vast majority of patients improved postoperatively. The complication rate was low: 1.2% of patients required revision PFDD at > 3 years postoperatively, 3.6% experienced other operative complications, and 0% had CSF leaks. CONCLUSIONS: The diversity of intradural findings and observations revealed in this study suggests that obstructive and compressive structural anomalies may be more common than previously reported among CM-I patients, both those patients with and those without syringomyelia and especially those with obstructive and compressive PICA branches. Although the authors cannot conclude that all these findings are necessarily pathological, further study may determine how they contribute to CM-I pathology and symptomatology in the setting of a compromised cisterna magna.

Global brain c-Fos profiling reveals major functional brain networks rearrangements after alcohol reexposure.

Many fundamental questions on alcohol use disorder (AUD) are frequently difficult to address by examining a single brain structure, but should be viewed from the whole brain perspective. c-Fos is a marker of neuronal activation. Global brain c-Fos profiling in rodents represents a promising platform to study brain functional networks rearrangements in AUD. We used a mouse model of alcohol drinking in IntelliCage. We trained mice to voluntarily drink alcohol, next subjected them to withdrawal and alcohol reexposure. We have developed a dedicated image computational workflow to identify c-Fos-positive cells in three-dimensional images obtained after whole-brain optical clearing and imaging in the light-sheet microscope. We provide a complete list of 169 brain structures with annotated c-Fos expression. We analyzed functional networks, brain modularity and engram index. Brain c-Fos levels in animals reexposed to alcohol were different from both control and binge drinking animals. Structures involved in reward processing, decision making and characteristic for addictive behaviors, such as precommissural nucleus, nucleus Raphe, parts of colliculus and tecta stood out particularly. Alcohol reexposure leads to a massive change of brain modularity including a formation of numerous smaller functional modules grouping structures involved in addiction development. Binge drinking can lead to substantial functional remodeling in the brain. We provide a list of structures that can be used as a target in pharmacotherapy but also point to the networks and modules that can hold therapeutic potential demonstrated by a clinical trial in patients.

Compromised Cranio-Spinal Suspension in Chiari Malformation Type 1: A Potential Role as Secondary Pathophysiology.

In Chiari Malformation Type I (CM1), low-lying tonsils obstruct the cisterna magna at the foramen magnum, thereby compromising the essential juncture between the cranial and spinal compartments. The anatomical obstruction of the cisterna magna inhibits bi-directional CSF flow as well as CSF pulse pressure equilibration between the intracranial compartment and the intraspinal compartment in response to instances of increased intracranial pressure. Less understood, however, are the roles of the spinal cord suspension structures at the craniocervical junction which lend viscoelastic support to the spinal cord and tonsils, as well as maintain the anatomical integrity of the cisterna magna and the dura. These include extradural ligaments including the myodural bridges (MDBs), as well as intradural dentate ligaments and the arachnoid framework. We propose that when these elements are disrupted by the cisterna magna obstruction, tonsillar pathology, and altered CSF dynamics, there may arise a secondary pathophysiology of compromised and dysfunctional cranio-spinal suspension in CM1. We present intraoperative images and videos captured during surgical exposure of the craniocervical junction in CM1 to illustrate this proposal.

Strategies discovery in the active allothetic place avoidance task.

The Active Allothetic Place Avoidance task is an alternative setup to Morris Water Maze that allows studying spatial memory in a dynamic world in the presence of conflicting information. In this task, a rat, freely moving on a rotating circular arena, has to avoid a sector defined within the room frame where shocks are presented. While for Morris Water Maze several studies have identified animal strategies which specifically affect performance, there were no such studies for the Active Allothetic Place Avoidance task. Using standard machine learning methods, we were able to reveal for the first time, to the best of our knowledge, explainable strategies that the animals employ in this task and demonstrate that they can provide a high-level interpretation for performance differences between an animal group treated with silver nanoparticles (AgNPs) and the control group.

A Standards Organization for Open and FAIR Neuroscience: the International Neuroinformatics Coordinating Facility.

There is great need for coordination around standards and best practices in neuroscience to support efforts to make neuroscience a data-centric discipline. Major brain initiatives launched around the world are poised to generate huge stores of neuroscience data. At the same time, neuroscience, like many domains in biomedicine, is confronting the issues of transparency, rigor, and reproducibility. Widely used, validated standards and best practices are key to addressing the challenges in both big and small data science, as they are essential for integrating diverse data and for developing a robust, effective, and sustainable infrastructure to support open and reproducible neuroscience. However, developing community standards and gaining their adoption is difficult. The current landscape is characterized both by a lack of robust, validated standards and a plethora of overlapping, underdeveloped, untested and underutilized standards and best practices. The International Neuroinformatics Coordinating Facility (INCF), an independent organization dedicated to promoting data sharing through the coordination of infrastructure and standards, has recently implemented a formal procedure for evaluating and endorsing community standards and best practices in support of the FAIR principles. By formally serving as a standards organization dedicated to open and FAIR neuroscience, INCF helps evaluate, promulgate, and coordinate standards and best practices across neuroscience. Here, we provide an overview of the process and discuss how neuroscience can benefit from having a dedicated standards body.

Structural Attributes and Principles of the Neocortical Connectome in the Marmoset Monkey.

The marmoset monkey has become an important primate model in Neuroscience. Here, we characterize salient statistical properties of interareal connections of the marmoset cerebral cortex, using data from retrograde tracer injections. We found that the connectivity weights are highly heterogeneous, spanning 5 orders of magnitude, and are log-normally distributed. The cortico-cortical network is dense, heterogeneous and has high specificity. The reciprocal connections are the most prominent and the probability of connection between 2 areas decays with their functional dissimilarity. The laminar dependence of connections defines a hierarchical network correlated with microstructural properties of each area. The marmoset connectome reveals parallel streams associated with different sensory systems. Finally, the connectome is spatially embedded with a characteristic length that obeys a power law as a function of brain volume across rodent and primate species. These findings provide a connectomic basis for investigations of multiple interacting areas in a complex large-scale cortical system underlying cognitive processes.

What we can and what we cannot see with extracellular multielectrodes.

Extracellular recording is an accessible technique used in animals and humans to study the brain physiology and pathology. As the number of recording channels and their density grows it is natural to ask how much improvement the additional channels bring in and how we can optimally use the new capabilities for monitoring the brain. Here we show that for any given distribution of electrodes we can establish exactly what information about current sources in the brain can be recovered and what information is strictly unobservable. We demonstrate this in the general setting of previously proposed kernel Current Source Density method and illustrate it with simplified examples as well as using evoked potentials from the barrel cortex obtained with a Neuropixels probe and with compatible model data. We show that with conceptual separation of the estimation space from experimental setup one can recover sources not accessible to standard methods.

Informal Dementia Caregivers: Current Technology Use and Acceptance of Technology in Care.

(1) Background: Given the increased social isolation caused by the COVID-19 pandemic, the challenges faced by informal dementia caregivers have increased. An increasing use of technology, both in care and dementia clinical trials, depends upon caregivers' abilities as a user. Accordingly, the aim of our study was to verify the current technology (smartphone and computer) use and acceptance in care, regarding socio-demographic variables; (2) Methods: Questionnaires were distributed to 102 dementia caregivers, mostly of patients with moderate dementia; (3) Results: The majority of participants were women (63%), and large number of them used technological devices such as a smartphone (91%) or computer (81%). Results revealed differences between age, gender, and education level on technology acceptance. Interestingly, smartphone use and acceptance seemed to be feasible, regardless of age, whereas computer use was negatively correlated with age. Technology was perceived by respondents as most useful for patients' activities including locomotion, toileting, and meals; (4) Conclusions: The future of technology use in dementia care should indicate solutions tailored to individual characteristics such as new technology solutions (GPS trackers, smartphone apps, dietary intervention, and meal planning apps).

Network and synaptic mechanisms underlying high frequency oscillations in the rat and cat olfactory bulb under ketamine-xylazine anesthesia.

Wake-related ketamine-dependent high frequency oscillations (HFO) can be recorded in local field potentials (LFP) from cortical and subcortical regions in rodents. The mechanisms underlying their generation and occurrence in higher mammals are unclear. Unfortunately, anesthetic doses of pure ketamine attenuate HFO, which has precluded their investigation under anesthesia. Here, we show ketamine-xylazine (KX) anesthesia is associated with a prominent 80-130 Hz rhythm in the olfactory bulb (OB) of rats, whereas 30-65 Hz gamma power is diminished. Simultaneous LFP and thermocouple recordings revealed the 80-130 Hz rhythm was dependent on nasal respiration. This rhythm persisted despite surgical excision of the piriform cortex. Silicon probes spanning the dorsoventral aspect of the OB revealed this rhythm was strongest in ventral areas and associated with microcurrent sources about the mitral layer. Pharmacological microinfusion studies revealed dependency on excitatory-inhibitory synaptic activity, but not gap junctions. Finally, a similar rhythm occurred in the OB of KX-anesthetized cats, which shared key features with our rodent studies. We conclude that the activity we report here is driven by nasal airflow, local excitatory-inhibitory interactions, and conserved in higher mammals. Additionally, KX anesthesia is a convenient model to investigate further the mechanisms underlying wake-related ketamine-dependent HFO.

Histology-Based Average Template of the Marmoset Cortex With Probabilistic Localization of Cytoarchitectural Areas.

The rapid adoption of marmosets in neuroscience has created a demand for three dimensional (3D) atlases of the brain of this species to facilitate data integration in a common reference space. We report on a new open access template of the marmoset cortex (the Nencki-Monash, or NM template), representing a morphological average of 20 brains of young adult individuals, obtained by 3D reconstructions generated from Nissl-stained serial sections. The method used to generate the template takes into account morphological features of the individual brains, as well as the borders of clearly defined cytoarchitectural areas. This has resulted in a resource which allows direct estimates of the most likely coordinates of each cortical area, as well as quantification of the margins of error involved in assigning voxels to areas, and preserves quantitative information about the laminar structure of the cortex. We provide spatial transformations between the NM and other available marmoset brain templates, thus enabling integration with magnetic resonance imaging (MRI) and tracer-based connectivity data. The NM template combines some of the main advantages of histology-based atlases (e.g. information about the cytoarchitectural structure) with features more commonly associated with MRI-based templates (isotropic nature of the dataset, and probabilistic analyses). The underlying workflow may be found useful in the future development of 3D brain atlases that incorporate information about the variability of areas in species for which it may be impractical to ensure homogeneity of the sample in terms of age, sex and genetic background.

Nasal respiration is necessary for ketamine-dependent high frequency network oscillations and behavioral hyperactivity in rats.

Changes in oscillatory activity are widely reported after subanesthetic ketamine, however their mechanisms of generation are unclear. Here, we tested the hypothesis that nasal respiration underlies the emergence of high-frequency oscillations (130-180 Hz, HFO) and behavioral activation after ketamine in freely moving rats. We found ketamine 20 mg/kg provoked "fast" theta sniffing in rodents which correlated with increased locomotor activity and HFO power in the OB. Bursts of ketamine-dependent HFO were coupled to "fast" theta frequency sniffing. Theta coupling of HFO bursts were also found in the prefrontal cortex and ventral striatum which, although of smaller amplitude, were coherent with OB activity. Haloperidol 1 mg/kg pretreatment prevented ketamine-dependent increases in fast sniffing and instead HFO coupling to slower basal respiration. Consistent with ketamine-dependent HFO being driven by nasal respiration, unilateral naris blockade led to an ipsilateral reduction in ketamine-dependent HFO power compared to the control side. Bilateral nares blockade reduced ketamine-induced hyperactivity and HFO power and frequency. These findings suggest that nasal airflow entrains ketamine-dependent HFO in diverse brain regions, and that the OB plays an important role in the broadcast of this rhythm.

Open access resource for cellular-resolution analyses of corticocortical connectivity in the marmoset monkey.

Understanding the principles of neuronal connectivity requires tools for efficient quantification and visualization of large datasets. The primate cortex is particularly challenging due to its complex mosaic of areas, which in many cases lack clear boundaries. Here, we introduce a resource that allows exploration of results of 143 retrograde tracer injections in the marmoset neocortex. Data obtained in different animals are registered to a common stereotaxic space using an algorithm guided by expert delineation of histological borders, allowing accurate assignment of connections to areas despite interindividual variability. The resource incorporates tools for analyses relative to cytoarchitectural areas, including statistical properties such as the fraction of labeled neurons and the percentage of supragranular neurons. It also provides purely spatial (parcellation-free) data, based on the stereotaxic coordinates of 2 million labeled neurons. This resource helps bridge the gap between high-density cellular connectivity studies in rodents and imaging-based analyses of human brains.

Electrical Source Imaging in Freely Moving Rats: Evaluation of a 12-Electrode Cortical Electroencephalography System.

This work presents and evaluates a 12-electrode intracranial electroencephalography system developed at the National Institute of Mental Health (Klecany, Czech Republic) in terms of an electrical source imaging (ESI) technique in rats. The electrode system was originally designed for translational research purposes. This study demonstrates that it is also possible to use this well-established system for ESI, and estimates its precision, accuracy, and limitations. Furthermore, this paper sets a methodological basis for future implants. Source localization quality is evaluated using three approaches based on surrogate data, physical phantom measurements, and in vivo experiments. The forward model for source localization is obtained from the FieldTrip-SimBio pipeline using the finite-element method. Rat brain tissue extracted from a magnetic resonance imaging template is approximated by a single-compartment homogeneous tetrahedral head model. Four inverse solvers were tested: standardized low-resolution brain electromagnetic tomography, exact low-resolution brain electromagnetic tomography (eLORETA), linear constrained minimum variance (LCMV), and dynamic imaging of coherent sources. Based on surrogate data, this paper evaluates the accuracy and precision of all solvers within the brain volume using error distance and reliability maps. The mean error distance over the whole brain was found to be the lowest in the eLORETA solution through signal to noise ratios (SNRs) (0.2 mm for 25 dB SNR). The LCMV outperformed eLORETA under higher SNR conditions, and exhibiting higher spatial precision. Both of these inverse solvers provided accurate results in a phantom experiment (1.6 mm mean error distance across shallow and 2.6 mm across subcortical testing dipoles). Utilizing the developed technique in freely moving rats, an auditory steady-state response experiment provided results in line with previously reported findings. The obtained results support the idea of utilizing a 12-electrode system for ESI and using it as a solid basis for the development of future ESI dedicated implants.

The olfactory bulb is a source of high-frequency oscillations (130-180 Hz) associated with a subanesthetic dose of ketamine in rodents.

High-frequency neuronal population oscillations (HFO, 130-180 Hz) are robustly potentiated by subanesthetic doses of ketamine. This frequency band has been recorded in functionally and neuroanatomically diverse cortical and subcortical regions, notably ventral striatal areas. However, the locus of generation remains largely unknown. There is compelling evidence that olfactory regions can drive oscillations in distant areas. Here we tested the hypothesis that the olfactory bulb (OB) is a locus for the generation of HFO following a subanesthetic dose of ketamine. The effect of ketamine on the electrophysiological activity of the OB and ventral striatum of male Wistar rats was examined using field potential and unit recordings, local inhibition, naris blockade, current source density and causality estimates. Ketamine-HFO was of larger magnitude and was phase-advanced in the OB relative to ventral striatum. Granger causality analysis was consistent with the OB as the source of HFO. Unilateral local inhibition of the OB and naris blockade both attenuated HFO recorded locally and in the ventral striatum. Within the OB, current source density analysis revealed HFO current dipoles close to the mitral layer and unit firing of mitral/tufted cells was phase locked to HFO. Our results reveal the OB as a source of ketamine-HFO which can contribute to HFO in the ventral striatum, known to project diffusely to many other brain regions. These findings provide a new conceptual understanding on how changes in olfactory system function may have implications for neurological disorders involving NMDA receptor dysfunction such as schizophrenia and depression.

Unidirectional monosynaptic connections from auditory areas to the primary visual cortex in the marmoset monkey.

Until the late twentieth century, it was believed that different sensory modalities were processed by largely independent pathways in the primate cortex, with cross-modal integration only occurring in specialized polysensory areas. This model was challenged by the finding that the peripheral representation of the primary visual cortex (V1) receives monosynaptic connections from areas of the auditory cortex in the macaque. However, auditory projections to V1 have not been reported in other primates. We investigated the existence of direct interconnections between V1 and auditory areas in the marmoset, a New World monkey. Labelled neurons in auditory cortex were observed following 4 out of 10 retrograde tracer injections involving V1. These projections to V1 originated in the caudal subdivisions of auditory cortex (primary auditory cortex, caudal belt and parabelt areas), and targeted parts of V1 that represent parafoveal and peripheral vision. Injections near the representation of the vertical meridian of the visual field labelled few or no cells in auditory cortex. We also placed 8 retrograde tracer injections involving core, belt and parabelt auditory areas, none of which revealed direct projections from V1. These results confirm the existence of a direct, nonreciprocal projection from auditory areas to V1 in a different primate species, which has evolved separately from the macaque for over 30 million years. The essential similarity of these observations between marmoset and macaque indicate that early-stage audiovisual integration is a shared characteristic of primate sensory processing.

A three-dimensional stereotaxic atlas of the gray short-tailed opossum (Monodelphis domestica) brain.

The gray short-tailed opossum (Monodelphis domestica) is a small marsupial gaining recognition as a laboratory animal in biomedical research. Despite numerous studies on opossum neuroanatomy, a consistent and comprehensive neuroanatomical reference for this species is still missing. Here we present the first three-dimensional, multimodal atlas of the Monodelphis opossum brain. It is based on four complementary imaging modalities: high resolution ex vivo magnetic resonance images, micro-computed tomography scans of the cranium, images of the face of the cutting block, and series of sections stained with the Nissl method and for myelinated fibers. Individual imaging modalities were reconstructed into a three-dimensional form and then registered to the MR image by means of affine and deformable registration routines. Based on a superimposition of the 3D images, 113 anatomical structures were demarcated and the volumes of individual regions were measured. The stereotaxic coordinate system was defined using a set of cranial landmarks: interaural line, bregma, and lambda, which allows for easy expression of any location within the brain with respect to the skull. The atlas is released under the Creative Commons license and available through various digital atlasing web services.