Motor learning and flexibility allow animals to perform routine actions efficiently while keeping them flexible. A number of paradigms are used to test cognitive flexibility, but not many of them focus specifically on the learning of complex motor sequences and their flexibility. While many tests use operant or touchscreen boxes that offer high throughput and reproducibility, the motor actions themselves are mostly simple presses of a designated lever. To focus more on motor actions during the operant task and to probe the flexibility of these well trained actions, we developed a new operant paradigm for mice, the “timed sequence task.” The task requires mice to learn a sequence of lever presses that have to be emitted in precisely defined time limits. After training, the required pressing sequence and/or timing of individual presses is modified to test the ability of mice to alter their previously trained motor actions. We provide a code for the new protocol that can be used and adapted to common types of...

The retinas of the vast majority of vertebrate species are termed “duplex,” that is, they contain both rod and cone photoreceptor neurons in different ratios. The retina of little skate ( Leucoraja erinacea ) is a rarity among vertebrates because it contains only a single photoreceptor cell type and is thus “simplex.” This unique retina provides us with an important comparative model and an exciting opportunity to study retinal circuitry within the context of a visual system with a single photoreceptor cell type. What is perhaps even more intriguing is the fact that the Leucoraja retina is able use that single photoreceptor cell type to function under both scotopic and photopic ranges of illumination. Although some ultrastructural characteristics of skate photoreceptors have been examined previously, leading to a general description of them as “rods” largely based on outer segment (OS) morphology and rhodopsin expression, a detailed study of the fine anatomy of the entire cell and its synaptic connectivity...

The Drosophila mushroom body (MB) is an important model system for studying the synaptic mechanisms of associative learning. In this system, coincidence of odor-evoked calcium influx and dopaminergic input in the presynaptic terminals of Kenyon cells (KCs), the principal neurons of the MB, triggers long-term depression (LTD), which plays a critical role in olfactory learning. However, it is controversial whether such synaptic plasticity is accompanied by a corresponding decrease in odor-evoked calcium activity in the KC presynaptic terminals. Here, we address this question by inducing LTD by pairing odor presentation with optogenetic activation of dopaminergic neurons (DANs). This allows us to rigorously compare the changes at the presynaptic and postsynaptic sites in the same conditions. By imaging presynaptic acetylcholine release in the condition where LTD is reliably observed in the postsynaptic calcium signals, we show that neurotransmitter release from KCs is depressed selectively in the MB compartme...

Depression is a frequent and serious illness, and stress is considered the main risk factor for its onset. First-line antidepressants increase serotonin (5-hydroxytryptamine; 5-HT) levels in the brain. We previously reported that an N -acetyltransferase, Shati/Nat8l, is upregulated in the dorsal striatum (dSTR) of stress-susceptible mice exposed to repeated social defeat stress (RSDS) and that dSTR Shati/Nat8l overexpression in mice (dSTR-Shati OE) induces stress vulnerability and local reduction in 5-HT content. Male mice were used in this study, and we found that dSTR 5-HT content decreased in stress-susceptible but not in resilient mice. Moreover, vulnerability to stress in dSTR-Shati OE mice was suppressed by the activation of serotonergic neurons projecting from the dorsal raphe nucleus (dRN) to the dSTR, followed by upregulation of 5-HT content in the dSTR using designer receptors exclusively activated by designer drugs (DREADD). We evaluated the role of GABA in modulating the serotonergic system in ...

Lysosomes are acidic organelles that traffic throughout neurons delivering catabolic enzymes to distal regions of the cell and maintaining degradative demands. Loss of function mutations in the gene GBA encoding the lysosomal enzyme glucocerebrosidase (GCase) cause the lysosomal storage disorder Gaucher’s disease (GD) and are the most common genetic risk factor for synucleinopathies like Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). GCase degrades the membrane lipid glucosylceramide (GlcCer) and mutations in GBA , or inhibiting its activity, results in the accumulation of GlcCer and disturbs the composition of the lysosomal membrane. The lysosomal membrane serves as the platform to which intracellular trafficking complexes are recruited and activated. Here, we investigated whether lysosomal trafficking in axons was altered by inhibition of GCase with the pharmacological agent Conduritol B Epoxide (CBE). Using live cell imaging in human male induced pluripotent human stem cell (iPSC)-derived...

Intracranial electroencephalography (iEEG) provides a unique opportunity to record and stimulate neuronal populations in the human brain. A key step in neuroscience inference from iEEG is localizing the electrodes relative to individual subject anatomy and identified regions in brain atlases. We describe a new software tool, Your Advanced Electrode Localizer (YAEL), that provides an integrated solution for every step of the electrode localization process. YAEL is compatible with all common data formats to provide an easy-to-use, drop-in replacement for problematic existing workflows that require users to grapple with multiple programs and interfaces. YAEL's automatic extrapolation and interpolation functions speed localization, especially important in patients with many implanted stereotactic (sEEG) electrode shafts. The graphical user interface is presented in a web browser for broad compatibility and includes an interactive 3D viewer for easier localization of nearby sEEG contacts. After localization is ...

Traumatic brain injury (TBI) affects millions of people annually and is a leading cause of long-term disability. Individuals with this condition commonly manifest behavioral, psychiatric, and cognitive dysfunctions, yet there is inadequate understanding of underlying mechanisms, posing challenges for effective treatments. TBI often arises from physical trauma to the head resulting in focal or diffuse injury, long-term cell loss, and tissue damage depending on injury type. Focal injuries can be modeled with the controlled cortical impact (CCI), while fluid percussion injury (FPI) models diffuse concussive injuries. Furthermore, each type of injury can be further classified based on severity (e.g., mild, moderate, and severe), each with their own unique pathophysiology. In mild TBI, diffuse injury leads to cell loss, diffuse axonal injury, and related circuit alterations in both afferent and efferent networks connecting to the injured cortical area (Krishna et al., 2020). It is recognized that dysfunction of...

In the article “Time Course of Alterations in Adult Spinal Motoneuron Properties in the SOD1(G93A) Mouse Model of ALS,” by Seoan Huh, Charles J. Heckman, and Marin Manuel, which was published online on February 25, 2021, Figure 8 appeared incorrectly. A sign error occurred when calculating the effect …

Respiratory sinus arrhythmia (RSA), the natural variation in heart rate synchronized with respiration, has been extensively studied in emotional and cognitive contexts. Various time or frequency-based methods using the cardiac signal have been proposed to analyze RSA. In this study, we present a novel approach that combines respiratory phase and heart rate to enable a more detailed analysis of RSA and its dynamics throughout the respiratory cycle. To facilitate the application of this method, we have implemented it in an open-source Python toolbox called physio. This toolbox includes essential functionalities for processing electrocardiogram (ECG) and respiratory signals, while also introducing this new approach for RSA analysis. Inspired by previous research conducted by our group, this method enables a cycle-by-cycle analysis of RSA providing the possibility to correlate any respiratory feature to any RSA feature. By employing this approach, we aim to gain a more accurate understanding of the neural mech...

During free viewing, we move our eyes and fixate on objects to recognize the visual scene of our surroundings. To investigate the neural representation of objects in this process, we studied individual and population neuronal activity in three different visual regions of the brains of macaque monkeys ( Macaca fuscata ): the primary and secondary visual cortices (V1, V2) and the inferotemporal cortex (IT). We designed a task where the animal freely selected objects in a stimulus image to fixate on while we examined the relationship between spiking activity, the order of fixations, and the fixated objects. We found that activity changed across repeated fixations on the same object in all three recorded areas, with observed reductions in firing rates. Furthermore, the responses of individual neurons became sparser and more selective with individual objects. The population activity for individual objects also became distinct. These results suggest that visual neurons respond dynamically to repeated input stimu...