Modulation of cortical representations of sensory and contextual information underlies aversive associative learning.

Cortical neurons encode both sensory and contextual information, yet it remains unclear how experiences modulate these cortical representations. Here, we demonstrate that trace eyeblink conditioning (TEC), an aversive associative-learning paradigm linking conditioned (CS) with unconditioned stimuli (US), finely tunes cortical coding at both population and single-neuron levels. Initially, we show that the primary somatosensory cortex (S1) is necessary for TEC acquisition, as evidenced by local muscimol administration. At the population level, TEC enhances activity in a small subset (∼20%) of CS- or US-responsive primary neurons (rPNs) while diminishing activity in non-rPNs, including locomotion-tuned or unresponsive PNs. Crucially, TEC learning modulates the encoding of sensory versus contextual information in single rPNs: CS-responsive neurons become less responsive, while US-responsive neurons gain responses to CS. Moreover, we find that the cholinergic pathway, via nicotinic receptors, underlies TEC-induced modulations. These findings suggest that experiences dynamically tune cortical representations through cholinergic pathways.

Impact of enriched environment on motor performance and learning in mice.

Neuroscience heavily relies on animal welfare in laboratory rodents as it can significantly affect brain development, cognitive function and memory formation. Unfortunately, laboratory animals are often raised in artificial environments devoid of physical and social stimuli, potentially leading to biased outcomes in behavioural assays. To assess this effect, we examined the impact of social and physical cage enrichment on various forms of motor coordination. Our findings indicate that while enriched-housed animals did not exhibit faster learning in eyeblink conditioning, the peak timing of their conditioned responses was slightly, but significantly, improved. Additionally, enriched-housed animals outperformed animals that were housed in standard conditions in the accelerating rotarod and ErasmusLadder test. In contrast, we found no significant effect of enrichment on the balance beam and grip strength test. Overall, our data suggest that an enriched environment can improve motor performance and motor learning under challenging and/or novel circumstances, possibly reflecting an altered state of anxiety.

Neurite density of the hippocampus is associated with trace eyeblink conditioning latency in 4- to 6-year-olds.

Limited options exist to evaluate the development of hippocampal function in young children. Research has established that trace eyeblink conditioning (EBC) relies on a functional hippocampus. Hence, we set out to investigate whether trace EBC is linked to hippocampal structure, potentially serving as a valuable indicator of hippocampal development. Our study explored potential associations between individual differences in hippocampal volume and neurite density with trace EBC performance in young children. We used onset latency of conditioned responses (CR) and percentage of conditioned responses (% CR) as measures of hippocampal-dependent associative learning. Using a sample of typically developing children aged 4 to 6 years (N = 30; 14 girls; M = 5.70 years), participants underwent T1- and diffusion-weighted MRI scans and completed a 15-min trace eyeblink conditioning task conducted outside the MRI. % CR and CR onset latency were calculated based on all trials involving tone-puff presentations and tone-alone trials. Findings revealed a connection between greater left hippocampal neurite density and delayed CR onset latency. Children with higher neurite density in the left hippocampus tended to blink closer to the onset of the unconditioned stimulus, indicating that structural variations in the hippocampus were associated with more precise timing of conditioned responses. No other relationships were observed between hippocampal volume, cerebellum volume or neurite density, hippocampal white matter connectivity and any EBC measures. Preliminary results suggest that trace EBC may serve as a straightforward yet innovative approach for studying hippocampal development in young children and populations with atypical development.

Dynamic Changes in Local Activity and Network Interactions among the Anterior Cingulate, Amygdala, and Cerebellum during Associative Learning.

Communication between the cerebellum and forebrain structures is necessary for motor learning and has been implicated in a variety of cognitive functions. The exact nature of cerebellar-forebrain interactions supporting behavior and cognition is not known. We examined how local and network activity support learning by simultaneously recording neural activity in the cerebellum, amygdala, and anterior cingulate cortex while male and female rats were trained in trace eyeblink conditioning. Initially, the cerebellum and forebrain signal the contingency between external stimuli through increases in theta power and synchrony. Neuronal activity driving expression of the learned response was observed in the cerebellum and became evident in the anterior cingulate and amygdala as learning progressed. Aligning neural activity to the training stimuli or learned response provided a way to differentiate between learning-related activity driven by different mechanisms. Stimulus and response-related increases in theta power and coherence were observed across all three areas throughout learning. However, increases in slow gamma power and coherence were only observed when oscillations were aligned to the cerebellum-driven learned response. Percentage of learned responses, learning-related local activity, and slow gamma communication from cerebellum to forebrain all progressively increased during training. The relatively fast frequency of slow gamma provides an ideal mechanism for the cerebellum to communicate learned temporal information to the forebrain. This cerebellar response-aligned slow gamma then provides enrichment of behavior-specific temporal information to local neuronal activity in the forebrain. These dynamic network interactions likely support a wide range of behaviors and cognitive tasks that require coordination between the forebrain and cerebellum.SIGNIFICANCE STATEMENT This study presents new evidence for how dynamic learning-related changes in single neurons and neural oscillations in a cerebellar-forebrain network support associative motor learning. The current results provide an integrated mechanism for how bidirectional communication between the cerebellum and forebrain represents important external events and internal neural drive. This bidirectional communication between the cerebellum and forebrain likely supports a wide range of behaviors and cognitive tasks that require temporal precision.

Neurophysiology of cerebellar ataxias and gait disorders.

There are numerous forms of cerebellar disorders from sporadic to genetic diseases. The aim of this chapter is to provide an overview of the advances and emerging techniques during these last 2 decades in the neurophysiological tests useful in cerebellar patients for clinical and research purposes. Clinically, patients exhibit various combinations of a vestibulocerebellar syndrome, a cerebellar cognitive affective syndrome and a cerebellar motor syndrome which will be discussed throughout this chapter. Cerebellar patients show abnormal Bereitschaftpotentials (BPs) and mismatch negativity. Cerebellar EEG is now being applied in cerebellar disorders to unravel impaired electrophysiological patterns associated within disorders of the cerebellar cortex. Eyeblink conditioning is significantly impaired in cerebellar disorders: the ability to acquire conditioned eyeblink responses is reduced in hereditary ataxias, in cerebellar stroke and after tumor surgery of the cerebellum. Furthermore, impaired eyeblink conditioning is an early marker of cerebellar degenerative disease. General rules of motor control suggest that optimal strategies are needed to execute voluntary movements in the complex environment of daily life. A high degree of adaptability is required for learning procedures underlying motor control as sensorimotor adaptation is essential to perform accurate goal-directed movements. Cerebellar patients show impairments during online visuomotor adaptation tasks. Cerebellum-motor cortex inhibition (CBI) is a neurophysiological biomarker showing an inverse association between cerebellothalamocortical tract integrity and ataxia severity. Ataxic gait is characterized by increased step width, reduced ankle joint range of motion, increased gait variability, lack of intra-limb inter-joint and inter-segmental coordination, impaired foot ground placement and loss of trunk control. Taken together, these techniques provide a neurophysiological framework for a better appraisal of cerebellar disorders.

Synaptic Mechanisms of Delay Eyeblink Classical Conditioning: AMPAR Trafficking and Gene Regulation in an In Vitro Model.

An in vitro model of delay eyeblink classical conditioning was developed to investigate synaptic plasticity mechanisms underlying acquisition of associative learning. This was achieved by replacing real stimuli, such as an airpuff and tone, with patterned stimulation of the cranial nerves using an isolated brainstem preparation from turtle. Here, our primary findings regarding cellular and molecular mechanisms for learning acquisition using this unique approach are reviewed. The neural correlate of the in vitro eyeblink response is a replica of the actual behavior, and features of conditioned responses (CRs) resemble those observed in behavioral studies. Importantly, it was shown that acquisition of CRs did not require the intact cerebellum, but the appropriate timing did. Studies of synaptic mechanisms indicate that conditioning involves two stages of AMPA receptor (AMPAR) trafficking. Initially, GluA1-containing AMPARs are targeted to synapses followed later by replacement by GluA4 subunits that support CR expression. This two-stage process is regulated by specific signal transduction cascades involving PKA and PKC and is guided by distinct protein chaperones. The expression of the brain-derived neurotrophic factor (BDNF) protein is central to AMPAR trafficking and conditioning. BDNF gene expression is regulated by coordinated epigenetic mechanisms involving DNA methylation/demethylation and chromatin modifications that control access of promoters to transcription factors. Finally, a hypothesis is proposed that learning genes like BDNF are poised by dual chromatin features that allow rapid activation or repression in response to environmental stimuli. These in vitro studies have advanced our understanding of the cellular and molecular mechanisms that underlie associative learning.

Nondeclarative associative learning in Alzheimer's disease: An overview of eyeblink, fear, and other emotion-based conditioning.

Alzheimer's disease is a neurodegenerative disorder that is characterized by progressive cognitive decline, particularly in declarative memory, and the presence of ß-amyloid plaques, neurofibrillary tangles, and cortical atrophy (especially in the temporal lobe). Unlike the relationship between the temporal cortex and declarative memory, nondeclarative memories (e.g., motor, fear, and other emotion-based memories) involve distinct neural structures. The present review investigates nondeclarative associative learning ability in Alzheimer's disease. We discuss eyeblink conditioning, fear conditioning, and other emotion-based learning and present the functions and brain areas that are involved in each type of learning. Evidence suggests that nondeclarative learning is also affected by Alzheimer's disease, although some forms of learning may be relatively preserved. Details about each nondeclarative associative learning process and the implications of these findings are presented.

A computational passage-of-time model of the cerebellar Purkinje cell in eyeblink conditioning.

The cerebellar Purkinje cell controlling eyeblinks can learn, remember, and reproduce the interstimulus interval in a classical conditioning paradigm. Given temporally separated inputs, the cerebellar Purkinje cell learns to pause its tonic inhibition of a motor pathway with high temporal precision so that an overt blink occurs at the right time. Most models place the passage-of-time representation in upstream network effects. Yet, bypassing the upstream network and directly stimulating the Purkinje cell's pre-synaptic fibers during conditioning still causes acquisition of a well-timed response. Additionally, while network models are sensitive to variance in the temporal structure of probe stimulation, in vivo findings suggest that the acquired Purkinje cell response is not. Such findings motivate alternative approaches to modeling neural function. Here, we present a proof-of-principle model of the passage-of-time which is internal to the Purkinje cell and is invariant to probe structure. The model is consistent with puzzling findings, accurately recapitulates Purkinje cell firing during classical conditioning and makes testable electrophysiological predictions.

Dataset of eyeblink conditioning in mice treated with the selective mGluR1 antagonist JNJ16259685.

Eyeblink conditioning is associated with motor learning, which requires the cerebellum and the brainstem. This article provides behavioral data on whether JNJ16259685, a selective metabotropic glutamate receptor type 1 (mGluR1) antagonist, affects eyeblink conditioning in wild-type mice (C57BL/6 J strain). The dataset contains four types of behavioral outputs pertinent to eyeblink conditioning. We used a t-test and an analysis of variance (ANOVA) to analyze the percentage of conditioned responses (CR%), peak CR latencies, onset CR latencies, and electromyography (EMG) amplitudes. The information obtained in this dataset adds to our knowledge of the molecular mechanisms underlying eyeblink conditioning and can prove beneficial for investigators studying the pharmacological effects of mGluR1 on motor learning. Future research might use this dataset as a basis for conducting experiments with different JNJ16259685 doses, administration methods, and durations than the ones used in the described procedures.

Pre-ataxic loss of intrinsic plasticity and motor learning in a mouse model of SCA1.

Spinocerebellar ataxias are neurodegenerative diseases, the hallmark symptom of which is the development of ataxia due to cerebellar dysfunction. Purkinje cells, the principal neurons of the cerebellar cortex, are the main cells affected in these disorders, but the sequence of pathological events leading to their dysfunction is poorly understood. Understanding the origins of Purkinje cells dysfunction before it manifests is imperative to interpret the functional and behavioural consequences of cerebellar-related disorders, providing an optimal timeline for therapeutic interventions. Here, we report the cascade of events leading to Purkinje cells dysfunction before the onset of ataxia in a mouse model of spinocerebellar ataxia 1 (SCA1). Spatiotemporal characterization of the ATXN1[82Q] SCA1 mouse model revealed high levels of the mutant ATXN1[82Q] weeks before the onset of ataxia. The expression of the toxic protein first caused a reduction of Purkinje cells intrinsic excitability, which was followed by atrophy of Purkinje cells dendrite arborization and aberrant glutamatergic signalling, finally leading to disruption of Purkinje cells innervation of climbing fibres and loss of intrinsic plasticity of Purkinje cells. Functionally, we found that deficits in eyeblink conditioning, a form of cerebellum-dependent motor learning, precede the onset of ataxia, matching the timeline of climbing fibre degeneration and reduced intrinsic plasticity. Together, our results suggest that abnormal synaptic signalling and intrinsic plasticity during the pre-ataxia stage of spinocerebellar ataxias underlie an aberrant cerebellar circuitry that anticipates the full extent of the disease severity. Furthermore, our work indicates the potential for eyeblink conditioning to be used as a sensitive tool to detect early cerebellar dysfunction as a sign of future disease.

Choline Improves Neonatal Hypoxia-Ischemia Induced Changes in Male but Not Female Rats.

Choline is an essential nutrient with many roles in brain development and function. Supplementation of choline in early development can have long-lasting benefits. Our experiments aimed to determine the efficacy of choline supplementation in a postnatal day (PND) 10 rat model of neonatal hypoxia ischemia (HI) at term using both male and female rat pups. Choline (100 mg/kg) or saline administration was initiated the day after birth and given daily for 10 or 14 consecutive days. We determined choline's effects on neurite outgrowth of sex-specific cultured cerebellar granule cells after HI with and without choline. The magnitude of tissue loss in the cerebrum was determined at 72 h after HI and in adult rats. The efficacy of choline supplementation in improving motor ability and learning, tested using eyeblink conditioning, were assessed in young adult male and female rats. Overall, we find that choline improves neurite outgrowth, short-term histological measures and learning ability in males. Surprisingly, choline did not benefit females, and appears to exacerbate HI-induced changes.

Role of cerebellar cortex in associative learning and memory in guinea pigs.

Time-related cognitive function refers to the capacity of the brain to store, extract, and process specific information. Previous studies demonstrated that the cerebellar cortex participates in advanced cognitive functions, but the role of the cerebellar cortex in cognitive functions is unclear. We established a behavioral model using classical eyeblink conditioning to study the role of the cerebellar cortex in associative learning and memory and the underlying mechanisms. We performed an investigation to determine whether eyeblink conditioning could be established by placing the stimulating electrode in the middle cerebellar peduncle. Behavior training was performed using a microcurrent pulse as a conditioned stimulus to stimulate the middle cerebellar peduncle and corneal blow as an unconditioned stimulus. After 10 consecutive days of training, a conditioned response was successfully achieved in the Delay, Trace-200-ms, and Trace-300-ms groups of guinea pigs, with acquisition rates of >60%, but the Trace-400-ms and control groups did not achieve a conditioned stimulus-related blink conditioned response. It could be a good model for studying the function of the cerebellum during the establishment of eyeblink conditioning.

Eyeblink tract tracing with two strains of herpes simplex virus 1.

BACKGROUND: Neuroinvasive herpes simplex-1 (HSV-1) isolates including H129 and McIntyre cross at or near synapses labeling higher-order neurons directly connected to infected cells. H129 spreads predominately in the anterograde direction while McIntyre strains spread only in the retrograde direction. However, it is unknown if neurons are functional once infected with derivatives of H129 or McIntyre. NEW METHOD: We describe a previously unpublished HSV-1 recombinant derived from H129 (HSV-373) expressing mCherry fluorescent reporters and one new McIntyre recombinant (HSV-780) expressing the mCherry fluorophore and demonstrate how infections affect neuron viability. RESULTS AND COMPARISON WITH EXISTING METHODS: Each recombinant virus behaved similarly and spread to the target 4 days post-infection. We tested H129 recombinant infected neurons for neurodegeneration using Fluoro-jade C and found them to be necrotic as a result of viral infection. We performed dual inoculations with both HSV-772 and HSV-780 to identify cells comprising both the anterograde pathway and the retrograde pathway, respectively, of our circuit of study. We examined the presence of postsynaptic marker PSD-95, which plays a role in synaptic plasticity, in HSV-772 infected and in dual-infected rats (HSV-772 and HSV-780). PSD-95 reactivity decreased in HSV-772-infected neurons and dual-infected tissue had no PSD-95 reactivity. CONCLUSIONS: Infection by these new recombinant viruses traced the circuit of interest but functional studies of the cells comprising the pathway were not possible because viral-infected neurons died as a result of necrosis or were stripped of PSD-95 by the time the viral labels reached the target.

mGluR5 Is Substitutable for mGluR1 in Cerebellar Purkinje Cells for Motor Coordination, Developmental Synapse Elimination, and Motor Learning.

Group I metabotropic glutamate receptors (mGluRs) include mGluR1 and mGluR5, which are coupled to the Gq family of heterotrimeric G-proteins and readily activated by their selective agonist 3,5-dihydroxyphenilglycine (DHPG). mGluR1 and mGluR5 exhibit nearly complementary distributions spatially or temporally in the central nervous system (CNS). In adult cerebellar Purkinje cells (PCs), mGluR1 is a dominant group I mGluR and mGluR5 is undetectable. mGluR1 expression increases substantially during the first three weeks of postnatal development and remains high throughout adulthood. On the other hand, mGluR5 expression is observed during the first two postnatal weeks and then decreases. However, functional differences between mGluR1 and mGluR5 in the CNS remains to be elucidated. To address this issue, we generated "mGluR5-rescue" mice in which mGluR5 is specifically expressed in PCs in global mGluR1-knockout (KO) mice. mGluR5-rescue mice exhibited apparently normal motor coordination, developmental elimination of redundant climbing fiber (CF)-PC synapses, and delay eyeblink conditioning, which were severely impaired in mGluR1-KO mice. We concluded that mGluR5 is functionally comparable with mGluR1 in cerebellar PCs.

Sex-Dependent Effects of Chronic Microdrive Implantation on Acquisition of Trace Eyeblink Conditioning.

Neuroscience techniques, including in vivo recording, have allowed for a great expansion in knowledge; however, this technology may also affect the very phenomena researchers set out to investigate. Including both female and male mice in our associative learning experiments shed light on sex differences on the impact of chronic implantation of tetrodes on learning. While previous research showed intact female mice acquired trace eyeblink conditioning faster than male and ovariectomized females, implantation of chronic microdrive arrays showed sexually dimorphic effects on learning. Microdrive implanted male mice acquired the associative learning paradigm faster than both intact and ovariectomized females. These effects were not due to the weight of the drive alone, as there were no significant sex-differences in learning of animals that received "dummy drive" implants without tetrodes lowered into the brain. Tandem mass tag mass spectrometry and western blot analysis suggest that significant alterations in the MAPK pathway, acute inflammation, and brain derived neurotrophic factor may underlie these observed sex- and surgery-dependent effects on learning.

Cerebellar transcranial direct current stimulation modulates timing but not acquisition of conditioned eyeblink responses in SCA3 patients.

BACKGROUND: Delay eyeblink conditioning is an extensively studied motor learning paradigm that critically depends on the integrity of the cerebellum. In healthy individuals, modulation of cerebellar excitability using transcranial direct current stimulation (tDCS) has been reported to alter the acquisition and/or timing of conditioned eyeblink responses (CRs). It remains unknown whether such effects can also be elicited in patients with cerebellar disorders. OBJECTIVE: To investigate if repeated sessions of cerebellar tDCS modify acquisition and/or timing of CRs in patients with spinocerebellar ataxia type 3 (SCA3) and to evaluate possible associations between disease severity measures and eyeblink conditioning parameters. METHODS: Delay eyeblink conditioning was examined in 20 mildly to moderately affected individuals with SCA3 and 31 healthy controls. After the baseline assessment, patients were randomly assigned to receive ten sessions of cerebellar anodal tDCS or sham tDCS (i.e., five days per week for two consecutive weeks). Patients and investigators were blinded to treatment allocation. The same eyeblink conditioning protocol was administered directly after the last tDCS session. The Scale for the Assessment and Rating of Ataxia (SARA), cerebellar cognitive affective syndrome scale (CCAS-S), and disease duration were used as clinical measures of disease severity. RESULTS: At baseline, SCA3 patients exhibited significantly fewer CRs than healthy controls. Acquisition was inversely associated with the number of failed CCAS-S test items but not with SARA score. Onset and peak latencies of CRs were longer in SCA3 patients and correlated with disease duration. Repeated sessions of cerebellar anodal tDCS did not affect CR acquisition, but had a significant treatment effect on both timing parameters. While a shift of CRs toward the conditioned stimulus was observed in the sham group (i.e., timing became more similar to that of healthy controls, presumably reflecting the effect of a second eyeblink conditioning session), anodal tDCS induced a shift of CRs in the opposite direction (i.e., toward the unconditioned stimulus). CONCLUSION: Our findings provide evidence that cerebellar tDCS is capable of modifying cerebellar function in SCA3 patients. Future studies should assess whether this intervention similarly modulates temporal processing in other degenerative ataxias.

A Critical Investigation of Cerebellar Associative Learning in Isolated Dystonia.

BACKGROUND: Impaired eyeblink conditioning is often cited as evidence for cerebellar dysfunction in isolated dystonia yet the results from individual studies are conflicting and underpowered. OBJECTIVE: To systematically examine the influence of dystonia, dystonia subtype, and clinical features over eyeblink conditioning within a statistical model which controlled for the covariates age and sex. METHODS: Original neurophysiological data from all published studies (until 2019) were shared and compared to an age- and sex-matched control group. Two raters blinded to participant identity rescored all recordings (6732 trials). After higher inter-rater agreement was confirmed, mean conditioning per block across raters was entered into a mixed repetitive measures model. RESULTS: Isolated dystonia (P = 0.517) and the subtypes of isolated dystonia (cervical dystonia, DYT-TOR1A, DYT-THAP1, and focal hand dystonia) had similar levels of eyeblink conditioning relative to controls. The presence of tremor did not significantly influence levels of eyeblink conditioning. A large range of eyeblink conditioning behavior was seen in both health and dystonia and sample size estimates are provided for future studies. CONCLUSIONS: The similarity of eyeblink conditioning behavior in dystonia and controls is against a global cerebellar learning deficit in isolated dystonia. Precise mechanisms for how the cerebellum interplays mechanistically with other key neuroanatomical nodes within the dystonic network remains an open research question. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Stimulus Generalization in Mice during Pavlovian Eyeblink Conditioning.

Here, we investigate stimulus generalization in a cerebellar learning paradigm, called eyeblink conditioning. Mice were conditioned to close their eyes in response to a 10-kHz tone by repeatedly pairing this tone with an air puff to the eye 250 ms after tone onset. After 10 consecutive days of training, when mice showed reliable conditioned eyelid responses to the 10-kHz tone, we started to expose them to tones with other frequencies, ranging from 2 to 20 kHz. We found that mice had a strong generalization gradient, whereby the probability and amplitude of conditioned eyelid responses gradually decreases depending on the dissimilarity with the 10-kHz tone. Tones with frequencies closest to 10 kHz evoked the most and largest conditioned eyelid responses and each step away from the 10-kHz tone resulted in fewer and smaller conditioned responses (CRs). In addition, we found that tones with lower frequencies resulted in CRs that peaked earlier after tone onset compared with those to tones with higher frequencies. Together, our data show prominent generalization patterns in cerebellar learning. Since the known function of cerebellum is rapidly expanding from pure motor control to domains that include cognition, reward-learning, fear-learning, social function, and even addiction, our data imply generalization controlled by cerebellum in all these domains.

Diet-induced Alzheimer's-like syndrome in the rabbit.

INTRODUCTION: Although mouse models of Alzheimer's disease (AD) have increased our understanding of the molecular basis of the disease, none of those models represent late-onset Alzheimer's Disease which accounts for >90% of AD cases, and no therapeutics developed in the mouse (with the possible exceptions of aduhelm/aducanumab and gantenerumab) have succeeded in preventing or reversing the disease. This technology has allowed much progress in understanding the molecular basis of AD. To further enhance our understanding, we used wild-type rabbit (with a nearly identical amino acid sequence for amyloid as in humans) to model LOAD by stressing risk factors including age, hypercholesterolemia, and elevated blood glucose levels (BGLs), upon an ε3-like isoform of apolipoprotein. We report a combined behavioral, imaging, and metabolic study using rabbit as a non-transgenic model to examine effects of AD-related risk factors on cognition, intrinsic functional connectivity, and magnetic resonance-based biomarkers of neuropathology. METHODS: Aging rabbits were fed a diet enriched with either 2% cholesterol or 10% fat/30% fructose. Monthly tests of novel object recognition (NOR) and object location memory (OLM) were administered to track cognitive impairment. Trace eyeblink conditioning (EBC) was administered as a final test of cognitive impairment. Magnetic resonance imaging (MRI) was used to obtain resting state connectivity and quantitative parametric data (R2*). RESULTS: Experimental diets induced hypercholesterolemia or elevated BGL. Both experimental diets induced statistically significant impairment of OLM (but not NOR) and altered intrinsic functional connectivity. EBC was more impaired by fat/fructose diet than by cholesterol. Whole brain and regional R2* MRI values were elevated in both experimental diet groups relative to rabbits on the control diet. DISCUSSION: We propose that mechanisms underlying LOAD can be assessed by stressing risk factors for inducing AD and that dietary manipulations can be used to assess etiological differences in the pathologies and effectiveness of potential therapeutics against LOAD. In addition, non-invasive MRI in awake, non-anesthetized rabbits further increases the translational value of this non-transgenic model to study AD.

Ventromedial Thalamus-Projecting DCN Neurons Modulate Associative Sensorimotor Responses in Mice.

The deep cerebellar nuclei (DCN) integrate various inputs to the cerebellum and form the final cerebellar outputs critical for associative sensorimotor learning. However, the functional relevance of distinct neuronal subpopulations within the DCN remains poorly understood. Here, we examined a subpopulation of mouse DCN neurons whose axons specifically project to the ventromedial (Vm) thalamus (DCNVm neurons), and found that these neurons represent a specific subset of DCN units whose activity varies with trace eyeblink conditioning (tEBC), a classical associative sensorimotor learning task. Upon conditioning, the activity of DCNVm neurons signaled the performance of conditioned eyeblink responses (CRs). Optogenetic activation and inhibition of the DCNVm neurons in well-trained mice amplified and diminished the CRs, respectively. Chemogenetic manipulation of the DCNVm neurons had no effects on non-associative motor coordination. Furthermore, optogenetic activation of the DCNVm neurons caused rapid elevated firing activity in the cingulate cortex, a brain area critical for bridging the time gap between sensory stimuli and motor execution during tEBC. Together, our data highlights DCNVm neurons' function and delineates their kinematic parameters that modulate the strength of associative sensorimotor responses.