Drosophila odorant receptors (Ors) are ligand gated ion channels composed of a common receptor subunit Or co-receptor (ORCO) and one of 62 “tuning” receptor subunits that confer odorant specificity to olfactory neuron responses. Like other sensory systems studied to date, exposing Drosophila olfactory neurons to activating ligands results in reduced responses to subsequent exposures through a process called desensitization. We recently showed that phosphorylation of serine 289 on the common Or subunit ORCO is required for normal peak olfactory neuron responses. Dephosphorylation of this residue occurs on prolonged odorant exposure, and underlies the slow modulation of olfactory neuron responses we term “slow desensitization.” Slow desensitization results in the reduction of peak olfactory neuron responses and flattening of dose–response curves, implicating changes in ORCOS289 phosphorylation state as an important modulator of olfactory neuron responses. Here, we report the identification of the primary kin...

Memories are rarely acquired under ideal conditions, rendering them vulnerable to profound omissions, errors, and ambiguities. Consistent with this, recent work using context fear conditioning has shown that memories formed after inadequate learning time display a variety of maladaptive properties, including overgeneralization to similar contexts. However, the neuronal basis of such poor learning and memory imprecision remains unknown. Using c-fos to track neuronal activity in male mice, we examined how these learning-dependent changes in context fear memory precision are encoded in hippocampal ensembles. We found that the total number of c-fos-encoding cells did not correspond with learning history but instead more closely reflected the length of the session immediately preceding c-fos measurement. However, using a c-fos-driven tagging method ( TRAP2 mouse line), we found that the degree of learning and memory specificity corresponded with neuronal activity in a subset of dentate gyrus cells that were act...

The planning and execution of head-beak movements are vital components of bird behavior. They require integration of sensory input and internal processes with goal-directed motor output. Despite its relevance, the neurophysiological mechanisms underlying action planning and execution outside of the song system are largely unknown. We recorded single-neuron activity from the associative endbrain area nidopallium caudolaterale (NCL) of two male carrion crows ( Corvus corone ) trained to plan and execute head-beak movements in a spatial delayed response task. The crows were instructed to plan an impending movement toward one of eight possible targets on the left or right side of a touchscreen. In a fraction of trials, the crows were prompted to plan a movement toward a self-chosen target. NCL neurons signaled the impending motion direction in instructed trials. Tuned neuronal activity during motor planning categorically represented the target side, but also specific target locations. As a marker of intentiona...

The central noradrenergic (NA) system is critical for maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer’s disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathological tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus (DG) is heavily innervated by LC-NA axons, where released norepinephrine (NE) acts on β-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex (EC) to facilitate long-term synaptic plasticity and memory formation. These synapses dysfunction in early AD prior to cognitive impairment. In the TgF344-AD rat model of AD, degeneration of LC-NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electroph...

The overexpression of calcineurin leads to astrocyte hyperactivation, neuronal death, and inflammation, which are characteristics often associated with pathological aging and Alzheimer’s disease. In this study, we tested the hypothesis that tacrolimus, a calcineurin inhibitor, prevents age-associated microstructural atrophy, which we measured using higher-order diffusion MRI, in the middle-aged beagle brain (n = 30, male and female). We find that tacrolimus reduces hippocampal (p = 0.001) and parahippocampal (p = 0.002) neurite density index (NDI), as well as protects against an age-associated increase in the parahippocampal (p = 0.007) orientation dispersion index (ODI). Tacrolimus also protects against an age-related decrease in fractional anisotropy (FA) in the prefrontal cortex (p<0.0001). We also show that these microstructural alterations precede cognitive decline and gross atrophy. These results support the idea that calcineurin inhibitors may have the potential to prevent aging-related pathology if...

Paramecium is a unicellular organism that swims in fresh water by beating thousands of cilia. When it is stimulated (mechanically, chemically, optically, thermally…), it often swims backward then turns and swims forward again. This “avoiding reaction” is triggered by a calcium-based action potential. For this reason, some authors have called Paramecium a “swimming neuron.” This review summarizes current knowledge about the physiological basis of behavior of Paramecium . Significance Statement Paramecium is a unicellular organism that swims in fresh water by beating thousands of cilia. When it is stimulated (mechanically, chemically, optically, thermally…), it often swims backward then turns and swims forward again. This “avoiding reaction” is triggered by a calcium-based action potential. For this reason, some authors have called Paramecium a “swimming neuron.” This review summarizes current knowledge about the physiological basis of behavior of Paramecium .

Qiaoling Cui, Xixun Du, Isaac Y. M. Chang, Arin Pamukcu, Varoth Lilascharoen, et al. (see pages [3966–3987][1]) The dorsal striatum is involved in action selection and sequencing. Whereas the dorsomedial subdivision is thought to mediate goal-directed actions, the dorsolateral subdivision is

The serotonergic system is strongly implicated in anxiety and depression, and it is the first-line target for pharmacological treatment ([Tamblyn et al., 2019][1]). Genetic factors predispose people to these disorders, but the anatomic and molecular diversity of the main serotonergic nuclei, the

The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and their roles in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting response of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson's disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a...

To thrive in dynamic environments, animals must be capable of rapidly and flexibly adapting behavioral responses to a changing context and internal state. Examples of behavioral flexibility include faster stimulus responses when attentive and slower responses when distracted. Contextual or state-dependent modulations may occur early in the cortical hierarchy and may be implemented via top-down projections from corticocortical or neuromodulatory pathways. However, the computational mechanisms mediating the effects of such projections are not known. Here, we introduce a theoretical framework to classify the effects of cell type-specific top-down perturbations on the information processing speed of cortical circuits. Our theory demonstrates that perturbation effects on stimulus processing can be predicted by intrinsic gain modulation, which controls the timescale of the circuit dynamics. Our theory leads to counterintuitive effects, such as improved performance with increased input variance. We tested the mod...