Neuron differentiation includes formation and outgrowth of neurites that differentiate into axons or dendrites. Directed neurite outgrowth is controlled by growth cones that protrude and retract actin-rich structures to sense environmental cues. These cues control local actin filament dynamics, steer growth cones towards attractants and away from repellents and navigate neurites through the developing brain. Rodent hippocampal neurons are widely used to study the mechanisms underlying neuron differentiation. Genetic manipulation of isolated neurons including gene inactivation or reporter gene expression can be achieved by classical transfections methods, but these methods are restricted to neurons cultured for several days, after neurite formation or outgrowth. Instead, electroporation allows gene manipulation prior to seeding. However, reporter gene expression usually takes up to 24 hours and time course of gene inactivation depends on the half live of the targeted mRNA and gene product. Hence, these meth...

Parkinson’s disease (PD) is a progressive neurodegenerative disease that is typically diagnosed late in its progression. There is a need for biomarkers suitable for monitoring the disease progression at earlier stages to guide the development of novel neuroprotective therapies. One potential biomarker, α-synuclein, has been found in both the familial cases of PD, as well as the sporadic cases and is considered a key feature of PD. α-synuclein is naturally present in the retina, and it has been suggested that early symptoms of the visual system may be used as a biomarker for PD. Here, we use a viral vector to induce a unilateral expression of human wildtype α-synuclein in rats as a mechanistic model of protein aggregation in PD. We employed functional magnetic resonance imaging (fMRI) to investigate whether adeno-associated virus (AAV) mediated expression of human wildtype α-synuclein alter functional activity in the visual system. 16 rats were injected with either AAV-α-synuclein (n=7) or AAV-null (n=9) i...

Some of us fortunate enough to have published a paper in the Journal of Neuroscience in its inaugural year (1981), have been asked to write a Progressions article addressing our views on the significance of the original work and how ideas about the topic of that work have evolved over the last 40 years. These questions cannot be effectively considered without placing them in the context of the incredible growth of the overall field of Neuroscience over these last four decades. For openers, in 1981, the Nobel Prize was awarded to three neuroscience superstars: Roger Sperry, David Hubel and Torsten Wiesel. Not a bad year to launch the Journal. With this as a backdrop, I divide this Progression into two parts. First, I discuss our original (1981) paper describing classical conditioning in Aplysia californica , and place our results in the context of the state of the field at the time. Second, I fast forward to the present and consider some of remarkable progress in the broad field of learning and memory that ...

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 .

Understanding how and where in the brain sentence-level meaning is constructed from words presents a major scientific challenge. Recent advances have begun to explain brain activation elicited by sentences using vector models of word meaning derived from patterns of word co-occurrence in text corpora. These studies have helped map out semantic representation across a distributed brain network spanning temporal, parietal, and frontal cortex. However, it remains unclear whether activation patterns within regions reflect unified representations of sentence-level meaning, as opposed to superpositions of context-independent component words. This is because models have typically represented sentences as “bags-of-words” that neglect sentence-level structure. To address this issue, we interrogated fMRI activation elicited as 240 sentences were read by 14 participants (9 female, 5 male), using sentences encoded by a recurrent deep artificial neural-network trained on a sentence inference task (InferSent). Recurrent...

Sleep has been shown to be critical for memory consolidation, with some research suggesting that certain memories are prioritized for consolidation. Initial strength of a memory appears to be an important boundary condition in determining which memories are consolidated during sleep. However, the role of consolidation-mediating oscillations, such as sleep spindles and slow oscillations, in this preferential consolidation has not been explored. Here, 54 human participants (76% female) studied pairs of words to three distinct encoding strengths, with recall being tested immediately following learning and again 6 h later. Thirty-six had a 2 h nap opportunity following learning, while the remaining 18 remained awake throughout. Results showed that, across 6 h awake, weakly encoded memories deteriorated the fastest. In the nap group, however, this effect was attenuated, with forgetting rates equivalent across encoding strengths. Within the nap group, consolidation of weakly encoded items was associated with fas...

At the request of the authors, The Journal of Neuroscience is retracting “The Sustained Antidepressant Effects of Ketamine are Independent of the Lateral Habenula,” by Xuelong Zhou, Chenjing Zhang, Jiamin Miao, Ziyang Chen, Hongquan Dong, and Cunming Liu, which appears on pages [4131–4140][1]

We have previously established that PV+ neurons and Npas1+ neurons are distinct neuron classes in the external globus pallidus (GPe): they have different topographical, electrophysiological, circuit, and functional properties. Aside from Foxp2+ neurons, which are a unique subclass within the Npas1+ class, we lack driver lines that effectively capture other GPe neuron subclasses. In this study, we examined the utility of Kcng4-Cre, Npr3-Cre, and Npy2r-Cre mouse lines (both males and females) for the delineation of GPe neuron subtypes. By using these novel driver lines, we have provided the most exhaustive investigation of electrophysiological studies of GPe neuron subtypes to date. Corroborating our prior studies, GPe neurons can be divided into two statistically distinct clusters that map onto PV+ and Npas1+ classes. By combining optogenetics and machine learning-based tracking, we showed that optogenetic perturbation of GPe neuron subtypes generated unique behavioral structures. Our findings further highl...