Dispositional mindfulness and its relationship to exercise motivation and experience.

Mindfulness is the psychological state of staying attuned to the present moment, without ruminating on past or future events, and allowing thoughts, feelings, or sensations to arise without judgment or attachment. Previous work has shown that heightened dispositional mindfulness is associated with the awareness of the importance of exercise, exercise self-efficacy, exercise motivation, and self-reported exercise level. However, more methodologically rigorous studies are needed to understand the relationship between mindfulness and the psychological mechanisms related to exercise motivation, including the identification of why individuals are motivated to engage in exercise, the subjective experience of exercise, and the propensity for exercise dependence and addiction. In this cross-sectional investigation, we utilized the framework of the Self-Determination Theory to examine the hypothesis that heightened dispositional mindfulness (as measured by the Mindful Attention Awareness Scale) would be associated with increased levels of exercise motivation that were derived by higher levels of autonomous self-regulation. Individuals were recruited from urban areas who self-reported either low (exercising 2 or fewer times per week for 20 min or less; n = 78) or moderate (exercising 1 or 2 times per week for 20 min or more; n = 127) levels of exercise engagement. As hypothesized, heightened dispositional mindfulness was significantly associated with heightened levels of exercise self-determination as measured by the Behavioral Regulations in Exercise Questionnaire, with this effect being driven by negative associations with amotivation, external regulation, and introjected regulation. Additionally, we found that heightened dispositional mindfulness was associated with lower levels of psychological distress upon exercise and decreased exercise dependence/addiction. Overall, increased dispositional mindfulness may support a healthy relationship with exercise. These findings have implications for the utility of mindfulness interventions to support the regulation of exercise behaviors in service of enhancing exercise motivation and engagement.

Recruitment and inhibitory action of hippocampal axo-axonic cells during behavior.

The axon initial segment of hippocampal pyramidal cells is a key subcellular compartment for action potential generation, under GABAergic control by the "chandelier" or axo-axonic cells (AACs). Although AACs are the only cellular source of GABA targeting the initial segment, their in vivo activity patterns and influence over pyramidal cell dynamics are not well understood. We achieved cell-type-specific genetic access to AACs in mice and show that AACs in the hippocampal area CA1 are synchronously activated by episodes of locomotion or whisking during rest. Bidirectional intervention experiments in head-restrained mice performing a random foraging task revealed that AACs inhibit CA1 pyramidal cells, indicating that the effect of GABA on the initial segments in the hippocampus is inhibitory in vivo. Finally, optogenetic inhibition of AACs at specific track locations induced remapping of pyramidal cell place fields. These results demonstrate brain-state-specific dynamics of a critical inhibitory controller of cortical circuits.

Preexisting hippocampal network dynamics constrain optogenetically induced place fields.

Memory models often emphasize the need to encode novel patterns of neural activity imposed by sensory drive. Prior learning and innate architecture likely restrict neural plasticity, however. Here, we test how the incorporation of synthetic hippocampal signals is constrained by preexisting circuit dynamics. We optogenetically stimulated small groups of CA1 neurons as mice traversed a chosen segment of a linear track, mimicking the emergence of place fields. Stimulation induced persistent place field remapping in stimulated and non-stimulated neurons. The emergence of place fields could be predicted from sporadic firing in the new place field location and the temporal relationship to peer neurons before the optogenetic perturbation. Circuit modification was reflected by altered spike transmission between connected pyramidal cells and inhibitory interneurons, which persisted during post-experience sleep. We hypothesize that optogenetic perturbation unmasked sub-threshold place fields. Plasticity in recurrent/lateral inhibition may drive learning through the rapid association of existing states.

Mechanisms of neural organization and rhythmogenesis during hippocampal and cortical ripples.

Neural activity during ripples has attracted great theoretical and experimental attention over the last three decades. Perhaps one reason for such interest is that ripples occur during quiet waking moments and during sleep, times when we reflect and dream about what has just occurred and what we expect to happen next. The hope is that understanding such 'offline' activity may yield insights into reflection, planning, and the purposes of sleep. This review focuses on the mechanisms by which neurons organize during these high-frequency events. In studying ripples, broader principles have emerged that relate intrinsic neural properties, network topology and synaptic plasticity in controlling neural activity. Ripples, therefore, serve as an excellent model for studying how properties of a neural network relate to neural dynamics. This article is part of the Theo Murphy meeting issue 'Memory reactivation: replaying events past, present and future'.

Head-mounted approaches for targeting single-cells in freely moving animals.

Neural network processing is usually studied using the spike times of many extracellularly recorded neurons. Elucidating the cellular-synaptic mechanisms underlying these firing patterns requires identifying and controlling single cells and assessing their inputs. Single cell glass electrode techniques (intracellular, patch and juxtacellular) are well suited to filling this gap, in terms of physiology, cell identity and behavior. However, they are typically limited to in vitro and immobilized in vivo experiments, primarily due to the necessity for mechanical stability and steep learning curves. Several approaches have been recently developed to extend these technologies to freely moving animals. Here we summarize the advantages and results for different methods of single neuron glass recordings in vivo. We further review three approaches used to date for single cell recording in freely moving animals: static anchor systems, manual mechanic drives and motorized drives. Finally, we highlight new technologies capable of expanding the utility of single neuron recording in freely moving animals.

Dual color optogenetic control of neural populations using low-noise, multishank optoelectrodes.

Optogenetics allows for optical manipulation of neuronal activity and has been increasingly combined with intra- and extra-cellular electrophysiological recordings. Genetically-identified classes of neurons are optically manipulated, though the versatility of optogenetics would be increased if independent control of distinct neural populations could be achieved on a sufficient spatial and temporal resolution. We report a scalable multi-site optoelectrode design that allows simultaneous optogenetic control of two spatially intermingled neuronal populations in vivo. We describe the design, fabrication, and assembly of low-noise, multi-site/multi-color optoelectrodes. Each shank of the four-shank assembly is monolithically integrated with 8 recording sites and a dual-color waveguide mixer with a 7 × 30 µm cross-section, coupled to 405 nm and 635 nm injection laser diodes (ILDs) via gradient-index (GRIN) lenses to meet optical and thermal design requirements. To better understand noise on the recording channels generated during diode-based activation, we developed a lumped-circuit modeling approach for EMI coupling mechanisms and used it to limit artifacts to amplitudes under 100 µV upto an optical output power of 450 µW. We implanted the packaged devices into the CA1 pyramidal layer of awake mice, expressing Channelrhodopsin-2 in pyramidal cells and ChrimsonR in paravalbumin-expressing interneurons, and achieved optical excitation of each cell type using sub-mW illumination. We highlight the potential use of this technology for functional dissection of neural circuits.

Excitation and inhibition compete to control spiking during hippocampal ripples: intracellular study in behaving mice.

High-frequency ripple oscillations, observed most prominently in the hippocampal CA1 pyramidal layer, are associated with memory consolidation. The cellular and network mechanisms underlying the generation of the rhythm and the recruitment of spikes from pyramidal neurons are still poorly understood. Using intracellular, sharp electrode recordings in freely moving, drug-free mice, we observed consistent large depolarizations in CA1 pyramidal cells during sharp wave ripples, which are associated with ripple frequency fluctuation of the membrane potential ("intracellular ripple"). Despite consistent depolarization, often exceeding pre-ripple spike threshold values, current pulse-induced spikes were strongly suppressed, indicating that spiking was under the control of concurrent shunting inhibition. Ripple events were followed by a prominent afterhyperpolarization and spike suppression. Action potentials during and outside ripples were orthodromic, arguing against ectopic spike generation, which has been postulated by computational models of ripple generation. These findings indicate that dendritic excitation of pyramidal neurons during ripples is countered by shunting of the membrane and postripple silence is mediated by hyperpolarizing inhibition.

GABAergic circuits mediate the reinforcement-related signals of striatal cholinergic interneurons.

Neostriatal cholinergic interneurons are believed to be important for reinforcement-mediated learning and response selection by signaling the occurrence and motivational value of behaviorally relevant stimuli through precisely timed multiphasic population responses. An important problem is to understand how these signals regulate the functioning of the neostriatum. Here we describe the synaptic organization of a previously unknown circuit that involves direct nicotinic excitation of several classes of GABAergic interneurons, including neuroptide Y-expressing neurogilaform neurons, and enables cholinergic interneurons to exert rapid inhibitory control of the activity of projection neurons. We also found that, in vivo, the dominant effect of an optogenetically reproduced pause-excitation population response of cholinergic interneurons was powerful and rapid inhibition of the firing of projection neurons that is coincident with synchronous cholinergic activation. These results reveal a previously unknown circuit mechanism that transmits reinforcement-related information of ChAT interneurons in the mouse neostriatal network.

Novel cerebrovascular pathology in mice fed a high cholesterol diet.

BACKGROUND: Hypercholesterolemia causes atherosclerosis in medium to large sized arteries. Cholesterol is less known for affecting the microvasculature and has not been previously reported to induce microvascular pathology in the central nervous system (CNS). RESULTS: Mice with a null mutation in the low-density lipoprotein receptor (LDLR) gene as well as C57BL/6J mice fed a high cholesterol diet developed a distinct microvascular pathology in the CNS that differs from cholesterol-induced atherosclerotic disease. Microvessel diameter was increased but microvascular density and length were not consistently affected. Degenerative changes and thickened vascular basement membranes were present ultrastructurally. The observed pathology shares features with the microvascular pathology of Alzheimer's disease (AD), including the presence of string-like vessels. Brain apolipoprotein E levels which have been previously found to be elevated in LDLR-/- mice were also increased in C57BL/6J mice fed a high cholesterol diet. CONCLUSION: In addition to its effects as an inducer of atherosclerosis in medium to large sized arteries, hypercholesterolemia also induces a microvascular pathology in the CNS that shares features of the vascular pathology found in AD. These observations suggest that high cholesterol may induce microvascular disease in a range of CNS disorders including AD.

Elevated plasma cholesterol does not affect brain Abeta in mice lacking the low-density lipoprotein receptor.

Epidemiological studies support an association between vascular risk factors, including hypercholesterolemia, and Alzheimer's disease (AD). Recently, there has been much interest in the possibility that hypercholesterolemia might directly promote beta-amyloid (Abeta) production. Indeed, in vitro studies have shown that increasing cellular cholesterol levels enhances Abeta production. However, studies in AD transgenic mouse models have not consistently found that elevated plasma cholesterol leads to increased Abeta production or deposition in vivo. In this study, we determined whether elevated peripheral cholesterol influences Abeta production in mice with a null mutation of the low-density lipoprotein receptor (LDLR). We show that dramatically elevated plasma cholesterol levels, whether induced by high cholesterol, high fat, or high fat/high cholesterol diets, did not affect either levels of brain Abeta40, Abeta42, or APP, or the Abeta42/40 or APP-CTF/APP ratios, nor substantially alter brain cholesterol levels. ApoE protein levels in brain were, however, elevated, in LDLR-/- mice by post-transcriptional mechanisms. Collectively, these studies argue that plasma cholesterol levels do not normally regulate production of brain Abeta.

Pepsin pretreatment allows collagen IV immunostaining of blood vessels in adult mouse brain.

While the brain vasculature can be imaged with many methods, immunohistochemistry has distinct advantages due to its simplicity and applicability to archival tissue. However, immunohistochemical staining of the murine brain vasculature in aldehyde fixed tissue has proven elusive and inconsistent using current protocols. Here we investigated whether antigen retrieval methods could improve vascular staining in the adult mouse brain. We found that pepsin digestion prior to immunostaining unmasked widespread collagen IV staining of the cerebrovasculature in the adult mouse brain. Pepsin treatment also unmasked widespread vascular staining with laminin, but only marginally improved isolectin B4 staining and did not enhance vascular staining with fibronectin, perlecan or CD146. Collagen IV immunoperoxidase staining was easily combined with cresyl violet counterstaining making it suitable for stereological analyses of both vascular and neuronal parameters in the same tissue section. This method should be widely applicable for labeling the brain vasculature of the mouse in aldehyde fixed tissue from both normal and pathological states.