Relapse is a major challenge to the treatment of substance use disorders. A progressive increase in cue-induced drug craving, termed incubation of craving, is observed after withdrawal from multiple drugs of abuse in humans and rodents. Incubation of cocaine craving involves the strengthening of excitatory synapses onto nucleus accumbens (NAc) medium spiny neurons via postsynaptic accumulation of high-conductance Ca2+-permeable AMPA receptors. This enhances reactivity to drug-associated cues and is required for the expression of incubation. Additionally, incubation of cocaine craving is associated with loss of the synaptic depression normally triggered by stimulation of metabotropic glutamate receptor 5 (mGlu5), leading to endocannabinoid production, and expressed presynaptically via cannabinoid receptor 1 activation. Previous studies have found alterations in mGlu5 and Homer proteins associated with the loss of this synaptic depression. Here we conducted coimmunoprecipitation studies to investigate associ...

Recent evidence suggests that alteration of axon initial segment (AIS) geometry (i.e., length or location along the axon) contributes to CNS dysfunction in neurological diseases. For example, AIS length is shorter in the prefrontal cortex of type 2 diabetic mice with cognitive impairment. To determine the key type 2 diabetes-related factor that produces AIS shortening we modified levels of insulin, glucose, or the reactive glucose metabolite methylglyoxal in cultures of dissociated cortices from male and female mice and quantified AIS geometry using immunofluorescent imaging of the AIS proteins AnkyrinG and βIV spectrin. Neither insulin nor glucose modification altered AIS length. Exposure to 100 but not 1 or 10 μm methylglyoxal for 24 h resulted in accumulation of the methylglyoxal-derived advanced glycation end-product hydroimidazolone and produced reversible AIS shortening without cell death. Methylglyoxal-evoked AIS shortening occurred in both excitatory and putative inhibitory neuron populations and i...

Forming long-term memories is crucial for adaptive behavior and survival in changing environments. The molecular consolidation processes which underlie the formation of these long-term memories are dependent on protein synthesis in excitatory and SST-expressing neurons. A centrally important, parallel process to this involves the removal of the memory constraint quinone reductase 2 (QR2), which has been recently shown to enhance memory consolidation for novel experiences in the cortex and hippocampus, via redox modulation. However, it is unknown within which cell type in the cortex removal of QR2 occurs, nor how this affects neuronal function. Here, we use novel taste learning in the mouse anterior insular cortex (aIC) to show that similarly to mRNA translation, QR2 removal occurs in excitatory and SST-expressing neurons. Interestingly, both novel taste and QR2 inhibition reduce excitability specifically within SST, but not excitatory neurons. Furthermore, reducing QR2 expression in SST, but not in PV or e...

Although we use our visual and tactile sensory systems interchangeably for object recognition on a daily basis, little is known about the mechanism underlying this ability. This study examined how 3D shape features of objects form two congruent and interchangeable visual and tactile perceptual spaces in healthy male and female participants. Since active exploration plays an important role in shape processing, a virtual reality environment was used to visually explore 3D objects called digital embryos without using the tactile sense. In addition, during the tactile procedure, blindfolded participants actively palpated a 3D-printed version of the same objects with both hands. We first demonstrated that the visual and tactile perceptual spaces were highly similar. We then extracted a series of 3D shape features to investigate how visual and tactile exploration can lead to the correct identification of the relationships between objects. The results indicate that both modalities share the same shape features to...

Spontaneous recognition memory tasks are widely used to assess cognitive function in rodents and have become commonplace in the characterization of rodent models of neurodegenerative, neuropsychiatric and neurodevelopmental disorders. Leveraging an animal’s innate preference for novelty, these tasks use object exploration to capture the what, where and when components of recognition memory. Choosing and optimizing objects is a key feature when designing recognition memory tasks. Although the range of objects used in these tasks varies extensively across studies, object features can bias exploration, influence task difficulty and alter brain circuit recruitment. Here, we discuss the advantages of using 3D-printed objects in rodent spontaneous recognition memory tasks. We provide strategies for optimizing their design and usage, and offer a repository of tested, open-source designs for use with commonly used rodent species. The easy accessibility, low-cost, renewability and flexibility of 3D-printed open-sou...

Prolonged exposure to a stimulus causes desensitization of cortical neurons and results in perceptual changes. One example of this phenomenon is contrast adaptation, in which perceived differences between light and dark regions of a stimulus decrease. Blakemore, Muncey, and Ridley reported evidence for the “perceptual fading of a stabilized cortical image” in a 1971 Nature paper. Our goal was to replicate their second experiment, in which adaptation was measured across many contrasts, and develop an active learning exercise for undergraduate students. The experiment was coded using an open-source python package and psychophysical data were collected from two observers. On each trial, a sinusoidally modulated luminance grating appeared above fixation, and the task of the observer was to adjust the contrast of a grating below fixation until the two appeared identical. Between trials in the adaptation condition, a high contrast grating was presented in the top location; no such grating appeared between trials...

Repetition is an indispensable component of motor skill acquisition. However, it is unknown how consistent repeated movement patterns must be to engage an implicit “use-dependent” learning mechanism. In this Registered Report, we tackled this question through a combination of computational modeling, simulations, and behavioral experiments involving visually-guided treadmill walking. Our hypotheses were formalized by two distinct computational models: in the two-process Strategy plus Use-Dependent model, use-dependent learning is viewed as a slowly updating and slowly decaying bias in the direction of repeated movements. The Adaptive Bayesian model frames use-dependent learning as an emergent property of quickly adapting prior probabilities of target step lengths. Critically, the Adaptive Bayesian model is much more sensitive to variable practice than the Strategy plus Use-Dependent model. To test these hypotheses, human participants ( N  = 18, 10 females) learned a novel asymmetric stepping pattern under t...

Humans can use their previous experience in form of statistical priors to improve decisions. It is, however, unclear how such priors are learned and represented. Importantly, it has remained elusive whether prior learning is independent of the sensorimotor system involved in the learning process or not, as both modality-specific and modality-general learning have been reported in the past. Here, we used a saccadic eye movement task to probe the learning and representation of a spatial prior across a few trials. In this task, learning occurs in an unsupervised manner and through encountering trial-by-trial visual hints drawn from a distribution centered on the target location. Using a model-comparison approach, we found that participants’ prior knowledge is largely represented in the form of their previous motor actions, with minimal influence from the previously seen visual hints. By using two different motor contexts for response (looking either at the estimated target location, or exactly opposite to it)...

Striatal activity is necessary to initiate and execute sequences of actions. The main excitatory input to the striatum comes from the cortex. While it is hypothesized that motor and premotor cortico-striatal projections are important to guide striatal activity during the execution of sequences of actions, technical limitations have made this challenging to address. Here, we implemented a task in mice that allows for the study of different moments to execute a serial order sequence consisting of two subsequences of actions. Using this task, we performed electrophysiological recordings in the premotor (M2) and primary motor (M1) cortices, and state-dependent optogenetic inhibitions of their cortico-striatal projections. We show that while both M2 and M1 contain activity modulations related to the execution of self-paced sequences, mainly, the premotor cortico-striatal projections contribute to the proper execution/structuring of these sequences.

Neurons are highly vulnerable to conditions of hypoxia-ischemia (HI) such as stroke or transient ischemic attacks. Recovery of cognitive and behavioral functions requires re-emergence of coordinated network activity, which, in turn, relies on the well-orchestrated interaction of pyramidal cells (PYRs) and interneurons. We therefore modelled HI in the mouse hippocampus, a particularly vulnerable region showing marked loss of PYR and fast-spiking interneurons (FSIs) after hypoxic-ischemic insults. Transient oxygen-glucose deprivation (OGD) in ex vivo hippocampal slices led to a rapid loss of neuronal activity and spontaneous network oscillations (sharp wave-ripple complexes; SPW-Rs), and to the occurrence of a spreading depolarization. Following reperfusion, both SPW-R and neuronal spiking resumed, but FSI activity remained strongly reduced compared with PYR. Whole-cell recordings in CA1 PYR revealed, however, a similar reduction of both EPSCs and IPSCs, leaving inhibition-excitation (I/E) balance unaltered....