Intracortical microstimulation (ICMS) is commonly used in many experimental and clinical paradigms; however, its effects on the activation of neurons are still not completely understood. To document the responses of cortical neurons in awake nonhuman primates to stimulation, we recorded single-unit activity while delivering single-pulse stimulation via Utah arrays implanted in primary motor cortex (M1) of three macaque monkeys. Stimuli between 5 and 50 μA delivered to single channels reliably evoked spikes in neurons recorded throughout the array with delays of up to 12 ms. ICMS pulses also induced a period of inhibition lasting up to 150 ms that typically followed the initial excitatory response. Higher current amplitudes led to a greater probability of evoking a spike and extended the duration of inhibition. The likelihood of evoking a spike in a neuron was dependent on the spontaneous firing rate as well as the delay between its most recent spike time and stimulus onset. Tonic repetitive stimulation bet...

The behavioral tagging (BT) hypothesis provides crucial insights into the mechanism of long-term memory (LTM) consolidation. Novelty exposure in BT is a decisive step in activating the molecular machinery of memory formation. Several studies have validated BT using different neurobehavioral tasks; however, the novelty given in all studies is open field (OF) exploration. Environment enrichment (EE) is another key experimental paradigm to explore the fundamentals of brain functioning. Recently, several studies have highlighted the importance of EE in enhancing cognition, LTM, and synaptic plasticity. Hence, in the present study, we investigated the effects of different types of novelty on LTM consolidation and plasticity-related protein (PRP) synthesis using the BT phenomenon. Novel object recognition (NOR) was used as the learning task for rodents (male Wistar rats), while OF and EE were two types of novel experiences provided to the rodents. Our results indicated that EE exposure efficiently leads to LTM c...

Investigation of rodent drinking behavior has provided insight into drivers of thirst, circadian rhythms, anhedonia, and drug and ethanol consumption. Traditional methods of recording fluid intake involve weighing bottles, which is cumbersome and lacks temporal resolution. Several open-source devices have been designed to improve drink monitoring, particularly for two-bottle choice tasks. However, beam-break sensors lack the ability to detect individual licks for bout microstructure analysis. Thus, we designed LIQ HD (Lick Instance Quantifier Home cage Device) with the goal of utilizing capacitive sensors to increase accuracy and analyze lick microstructure, building a device compatible with ventilated home cages, increasing scale with prolonged undisturbed recordings, and creating a design that is easy to build and use with an intuitive touchscreen graphical user interface. The system tracks two-bottle choice licking behavior in up to 18 rodent cages, or 36 single bottles, on a minute-to-minute timescale ...

Very preterm infants show low levels of insulin-like growth factor-1 (IGF-1), which is associated with postnatal growth restriction and poor neurological outcomes. It remains unknown whether supplemental IGF-1 may stimulate neurodevelopment in preterm neonates. Using cesarean-delivered preterm pigs as a model of preterm infants, we investigated the effects of supplemental IGF-1 on motor function and regional and cellular brain development. Pigs were treated with 2.25 mg/kg/day of recombinant human IGF-1/IGF binding protein 3 complex from birth until Day 5 or 9 before collection of brain samples for quantitative immunohistochemistry (IHC), RNA-seq and qPCR analyses. Brain protein synthesis was measured using in vivo labeling with [2H5] phenylalanine. We showed that the IGF-1 receptor was widely distributed in the brain and largely coexisted with immature neurons. Region-specific quantification of IHC labeling showed that IGF-1 treatment promoted neuronal differentiation, increased subcortical myelination, a...

A key assumption in studies of cortical functions is that excitatory principal neurons, but not inhibitory cells express calcium/calmodulin-dependent protein kinase II subunit α (CaMKIIα) resulting in a widespread use of CaMKIIα promoter-driven protein expression for principal cell manipulation and monitoring their activities. Using neuroanatomical and electrophysiological methods we demonstrate that in addition to pyramidal neurons, multiple types of cortical GABAegic cells are targeted by adeno-associated viral vectors (AAV) driven by the CaMKIIα promoter in both male and female mice. We tested the AAV5 and AAV9 serotype of viruses with either Channelrhodopsin 2-mCherry or Archaerhodopsin-T-GFP constructs, with different dilutions. We show that in all cases, the reporter proteins can visualize a large fraction of different interneuron types, including parvalbumin (PV), somatostatin (SST), neuronal nitric oxide synthase (nNOS), neuropeptide Y (NPY) and cholecystokinin (CCK)-containing GABAergic cells, whi...

When deciding while acting, such as sequentially selecting targets during naturalistic foraging, movement trajectories reveal the dynamics of the unfolding decision process. Ongoing and planned actions may impact decisions in these situations in addition to expected reward outcomes. Here, we test how strongly humans weigh and how fast they integrate individual constituents of expected value, namely the prior probability of an action (PROB) and the prior expected reward amount associated with an action (AMNT), when deciding based on the combination of both together during an ongoing movement. Unlike other decision-making studies, we focus on PROB and AMNT priors, and not final evidence, in that correct actions were either instructed or could be chosen freely. This means, there was no decision-making under risk. We show that both priors gradually influence movement trajectories already before mid-movement instructions of the correct target and bias free-choice behavior. These effects were consistently strong...

Brain stores new information by modifying connections between neurons. When new information is learnt, a group of neurons gets activated and they are connected to each other via synapses. Dendritic spines are protrusions along neuronal dendrites where excitatory synapses are located. Dendritic spines are the first structures to protrude out from the dendrite to reach out to other neurons and establish a new connection. Thus, it is expected that neuronal activity enhances spine initiation. However, the molecular mechanisms linking neuronal activity to spine initiation are poorly known. Membrane binding BAR domain proteins are involved in spine initiation, but it is not known whether neuronal activity affects BAR domain proteins. Here, we used bicuculline treatment to activate excitatory neurons in organotypic hippocampal slices. With this experimental setup we identified F-BAR domain containing Growth Arrest-Specific Protein (Gas7) as a novel spine initiation factor responding to neuron activity. Upon bicuc...

Vagal sensory neurons (VSNs) located in the nodose ganglion provide information, such as stomach stretch or the presence of ingested nutrients, to the caudal medulla via specialized cell types expressing unique marker genes. Here, we leverage VSN marker genes identified in adult mice to determine when specialized vagal subtypes arise developmentally and the trophic factors that shape their growth. Experiments to screen for trophic factor sensitivity revealed that brain derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF) robustly stimulate neurite outgrowth from VSNs in vitro . Perinatally, BDNF was expressed by neurons of the nodose ganglion itself, while GDNF was expressed by intestinal smooth muscle cells. Thus, BDNF may support VSNs locally, whereas GDNF may act as a target-derived trophic factor supporting the growth of processes at distal innervation sites in the gut. Consistent with this, expression of the GDNF receptor was enriched in VSN cell types that project to t...

The nasal epithelium houses a population of solitary chemosensory cells (SCCs). SCCs express bitter taste receptors and taste transduction signaling components and are innervated by peptidergic trigeminal polymodal nociceptive nerve fibers. Thus, nasal SCCs respond to bitter compounds, including bacterial metabolites, and these reactions evoke protective respiratory reflexes and innate immune and inflammatory responses. We tested whether SCCs are implicated in aversive behavior to specific inhaled nebulized irritants using a custom-built dual-chamber forced-choice device. The behavior of mice was recorded and analyzed for the time spent in each chamber. Wild-type (WT) mice exhibited an aversion to 10 mM denatonium benzoate (Den) or cycloheximide and spent more time in the control (saline) chamber. The SCC-pathway knockout (KO) mice did not exhibit such an aversion response. The bitter avoidance behavior of WT mice was positively correlated with the concentration increase of Den and the number of exposures....

Loss-of-function mutations in Reelin and DAB1 signaling pathways disrupt proper neuronal positioning in the cerebral neocortex and hippocampus, but the underlying molecular mechanisms remain elusive. Here we report that heterozygous yotari mice harboring a single autosomal recessive yotari mutation of Dab1 exhibited a thinner neocortical layer 1 than wild-type mice on postnatal day 7. However, a birth-dating study suggested that this reduction was not caused by failure of neuronal migration. In utero electroporation-mediated sparse labeling revealed that the superficial layer neurons of heterozygous yotari mice tended to elongate their apical dendrites within layer 2 than within layer 1. In addition, the CA1 pyramidal cell layer in the caudo-dorsal hippocampus was abnormally split in heterozygous yotari mice, and a birth-dating study revealed that this splitting was caused mainly by migration failure of late-born pyramidal neurons. Adeno-associated virus-mediated sparse labeling further showed that many py...