Lamina-specific population encoding of cutaneous signals in the spinal dorsal horn using multi-electrode arrays.

Key Points: Traditional, widely used in vivo electrophysiological techniques for the investigation of spinal processing of somatosensory information fail to account for the diverse functions of each lamina. To overcome this oversimplification, we have used multi-electrode arrays, in vivo, to simultaneously record neuronal activity across all laminae of the spinal dorsal horn. Multi-electrode arrays are sensitive enough to detect lamina- and region-specific encoding of different subtypes of afferent fibres and to detect short-lived changes in synaptic plasticity as measured by the application of cutaneous electrical stimulation of varying intensity and frequency.

Age-dependent plasticity in endocannabinoid modulation of pain processing through postnatal development.

Significant age- and experience-dependent remodelling of spinal and supraspinal neural networks occur, resulting in altered pain responses in early life. In adults, endogenous opioid peptide and endocannabinoid (ECs) pain control systems exist which modify pain responses, but the role they play in acute responses to pain and postnatal neurodevelopment is unknown. Here, we have studied the changing role of the ECs in the brainstem nuclei essential for the control of nociception from birth to adulthood in both rats and humans.

Manganese-enhanced magnetic resonance imaging depicts brain activity in models of acute and chronic pain: A new window to study experimental spontaneous pain?

Application of functional imaging techniques to animal models is vital to understand pain mechanisms, but is often confounded by the need to limit movement artefacts with anaesthesia, and a focus on evoked responses rather than clinically relevant spontaneous pain and related hyperalgesia. The aim of the present study was to investigate the potential of manganese-enhanced magnetic resonance imaging (MEMRI) to measure neural responses during on-going pain that underpins hyperalgesia in pre-clinical models of nociception. As a proof of concept that MEMRI is sensitive to the neural activity of spontaneous, intermittent behaviour, we studied a separate positive control group undergoing a voluntary running wheel experiment.

Optical imaging of the rat brain suggests a previously missing link between top-down and bottom-up nervous system function.

Optical imaging with voltage-sensitive dyes enables the visualization of extensive yet highly transient coalitions of neurons (assemblies) operating throughout the brain on a subsecond time scale. We suggest that operating at the mesoscale level of brain organization, neuronal assemblies may provide a functional link between "bottom-up" cellular mechanisms and "top-down" cognitive ones within anatomically defined regions. We demonstrate in rat brain slices how varying spatiotemporal dynamics of assemblies reveal differences not previously appreciated between: different stages of development in cortical versus subcortical brain areas, different sensory modalities (hearing versus vision), different classes of psychoactive drugs (anesthetics versus analgesics), different effects of anesthesia linked to hyperbaric conditions and, , depths of anesthesia.

(II) Physiological profiling of an endogenous peptide in the basal forebrain: Age-related bioactivity and blockade with a novel modulator.

Previous studies have suggested that neurodegeneration is an aberrant form of development, mediated by a novel peptide from the C-terminus of acetylcholinesterase (AChE). Using voltage-sensitive dye imaging we have investigated the effects of a synthetic version of this peptide in the in vitro rat basal forebrain, a key site of degeneration in Alzheimer's disease. The brain slice preparation enables direct visualisation in real-time of sub-second meso-scale neuronal coalitions ('Neuronal Assemblies') that serve as a powerful index of brain functional activity.

Developmental alterations in noxious-evoked EEG activity recorded from rat primary somatosensory cortex.

Primary somatosensory cortex (S1) contains a nociceptive map that localizes potential tissue damage on the body and encodes stimulus intensity. An objective and specific biomarker of pain however is currently lacking and is urgently required for use in non-verbal clinical populations as well as in the validation of pre-clinical pain models. Here we describe studies to see if the responses of the S1 in juvenile rats are different to those in the adult.

A quantification of the relationship between neuronal responses in the rat rostral ventromedial medulla and noxious stimulation-evoked withdrawal reflexes.

The rostral ventromedial medulla (RVM) regulates a range of involuntary behaviours but is most often associated with nociception via the action of pronociceptive ON cells and antinociceptive OFF cells. The phasic responses of ON and OFF cells determine whether or not incoming noxious signals provoke a withdrawal reflex, and previous studies have suggested that reflex RVM activity patterns actively shape motor output. Here we challenged the model by using juvenile rats, which are known to exhibit markedly different reflex responses compared with adults.

Risk-based learning games improve long-term retention of information among school pupils.

Risk heightens motivation and, if used appropriately, may have the potential to improve engagement in the classroom. We have developed a risk-based learning game for school pupils in order to test whether such learning games can improve later recall of information. The study was performed during a series of public engagement workshops delivered by undergraduate students.

Enhanced visual responses in the superior colliculus in an animal model of attention-deficit hyperactivity disorder and their suppression by D-amphetamine.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder characterized by overactivity, impulsiveness and attentional problems, including an increase in distractibility. A structure that is intimately linked with distractibility is the superior colliculus (SC), a midbrain sensory structure which plays a particular role in the production of eye and head movements. Although others have proposed the involvement of such diverse elements as the frontal cortex and forebrain noradrenaline in ADHD, given the role of the colliculus in distractibility and the increased distractibility in ADHD, we have proposed that distractibility in ADHD arises due to collicular sensory hyper-responsiveness.

Overcoming the barriers to greater public engagement.

Integrating science communication training into an undergraduate research project encourages greater academic involvement in public engagement, maximizes audience size, and provides high-quality research data.

Postnatal maturation of endogenous opioid systems within the periaqueductal grey and spinal dorsal horn of the rat.

Significant opioid-dependent changes occur during the fourth postnatal week in supraspinal sites (rostroventral medulla [RVM], periaqueductal grey [PAG]) that are involved in the descending control of spinal excitability via the dorsal horn (DH). Here we report developmentally regulated changes in the opioidergic signalling within the PAG and DH, which further increase our understanding of pain processing during early life. Microinjection of the μ-opioid receptor (MOR) agonist DAMGO (30 ng) into the PAG of Sprague-Dawley rats increased spinal excitability and lowered mechanical threshold to noxious stimuli in postnatal day (P)21 rats, but had inhibitory effects in adults and lacked efficacy in P10 pups.

An evaluation of in vivo voltage-sensitive dyes: pharmacological side effects and signal-to-noise ratios after effective removal of brain-pulsation artifacts.

In the current study, we investigated pharmacological side effects and signal-to-noise ratios (SNRs) of two commonly used voltage-sensitive dyes (VSDs): the blue dye RH-1691 (1 mg/ml) and the red dye di-4-ANEPPS (0.1 mg/ml), applied in vivo to the rat barrel cortex. Blue dyes are often favored over red dyes in in vivo studies due to their apparent superior SNR, partly because their fluorescence spectrum is farther away from the hemoglobin absorption spectrum, making them less prone to heartbeat-associated brain-pulsation artifacts (BPA).

Neurovascular coupling is brain region-dependent.

Despite recent advances in alternative brain imaging technologies, functional magnetic resonance imaging (fMRI) remains the workhorse for both medical diagnosis and primary research. Indeed, the number of research articles that utilise fMRI have continued to rise unabated since its conception in 1991, despite the limitation that recorded signals originate from the cerebral vasculature rather than neural tissue. Consequently, understanding the relationship between brain activity and the resultant changes in metabolism and blood flow (neurovascular coupling) remains a vital area of research.

Teaching medical students basic neurotransmitter pharmacology using primary research resources.

Teaching pharmacology to medical students has long been seen as a challenge, and one to which a number of innovative approaches have been taken. In this article, we describe and evaluate the use of primary research articles in teaching second-year medical students both in terms of the information learned and the use of the papers themselves. We designed a seminar where small groups of students worked on different neurotransmitters before contributing information to a plenary session.

Neuroscience: viable applications in education?

As a relatively young science, neuroscience is still finding its feet in potential collaborations with other disciplines. One such discipline is education, with the field of neuroeducation being on the horizon since the 1960s. However, although its achievements are now growing, the partnership has not been as successful as first hopes suggested it should be.

Environmental enrichment differentially modifies specific components of sensory-evoked activity in rat barrel cortex as revealed by simultaneous electrophysiological recordings and optical imaging in vivo.

Environmental enrichment of laboratory animals leads to multi-faceted changes to physiology, health and disease prognosis. An important and under-appreciated factor in enhancing cognition through environmental manipulation may be improved basic sensory function. Previous studies have highlighted changes in cortical sensory map plasticity but have used techniques such as electrophysiology, which suffer from poor spatial resolution, or optical imaging of intrinsic signals, which suffers from low temporal resolution.

Effects of urethane anaesthesia on sensory processing in the rat barrel cortex revealed by combined optical imaging and electrophysiology.

The spatiotemporal dynamics of neuronal assemblies evoked by sensory stimuli have not yet been fully characterised, especially the extent to which they are modulated by prevailing brain states. In order to examine this issue, we induced different levels of anaesthesia, distinguished by specific electroencephalographic indices, and compared somatosensory-evoked potentials (SEPs) with voltage-sensitive dye imaging (VSDI) responses in the rat barrel cortex evoked by whisker deflection. At deeper levels of anaesthesia, all responses were reduced in amplitude but, surprisingly, only VSDI responses exhibited prolonged activation resulting in a delayed return to baseline.

From scientific theory to classroom practice.

The importance of neuroscience in education is becoming widely recognized by both neuroscientists and educators. However, to date, there has been little effective collaboration between the two groups, resulting in the spread of ideas in education poorly based on neuroscience. For their part, educators are often too busy to develop sufficient scientific literacy, and neuroscientists are put off collaborations with risk of overinterpretation of their work.

A dynamic model of neurovascular coupling: implications for blood vessel dilation and constriction.

Neurovascular coupling in response to stimulation of the rat barrel cortex was investigated using concurrent multichannel electrophysiology and laser Doppler flowmetry. The data were used to build a linear dynamic model relating neural activity to blood flow. Local field potential time series were subject to current source density analysis, and the time series of a layer IV sink of the barrel cortex was used as the input to the model.

A dynamic causal model of the coupling between pulse stimulation and neural activity.

We present a dynamic causal model that can explain context-dependent changes in neural responses, in the rat barrel cortex, to an electrical whisker stimulation at different frequencies. Neural responses were measured in terms of local field potentials. These were converted into current source density (CSD) data, and the time series of the CSD sink was extracted to provide a time series response train.

Design and evaluation of a low-cost respiratory monitoring device for use with anaesthetized animals.

This report describes a simple, non-invasive electronic device that employs a compact accelerometer integrated circuit to transduce movements in the chest wall of an anaesthetized animal into an analogue signal that can be used to calculate the rate and relative depth of respiration. The device requires amplification by signal processing hardware/software which are common to most experimental laboratories. We assessed the sensitivity of the device by its ability to detect changes in respiratory patterns produced by modulating the depth of anaesthesia in isoflurane-anaesthetized Wistar rats.

Altered neurovascular coupling during information-processing states.

Brain imaging techniques rely on changes in blood flow, volume and oxygenation to infer the loci and magnitude of changes in activity. Although progress has been made in understanding the link between stimulus-evoked neural activity and haemodynamics, the extent to which neurovascular-coupling relationships remain constant during different states of baseline cortical activity is poorly understood. Optical imaging spectroscopy, laser Doppler flowmetry and electrophysiology were used to measure haemodynamics and neural activity in the barrel cortex of anaesthetized rats.

D-amphetamine depresses visual responses in the rat superior colliculus: a possible mechanism for amphetamine-induced decreases in distractibility.

Amphetamines can enhance sustained attention, and reduce distractibility, in normal subjects and patients with attentional-deficit/hyperactivity disorder (ADHD). Their mechanism of action in this regard is unknown, however one possibility is that the drugs affect the superior colliculus (SC), a structure with a clearly defined role in distractibility. The aim of the present studies was to explore the effect of systemically and locally administered d-amphetamine on visual responses in the superficial layers of the SC to wholefield light flashes in the rat, using local field potential and multi-unit recording.

Investigating the coupling between stimulation and neural activity: a dynamic modeling approach.

The objective of the present study was to build a dynamic model relating changes in neural responses in rat barrel cortex to an electrical whisker stimulation pulse train of varying frequencies. This work is part of a formal mathematical system currently being developed, which links stimulation to the Blood Oxygen Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) signal. Neural responses were measured in terms of local field potentials, which were then converted into current source density (CSD) data.

Cocaine preferentially enhances sensory processing in the upper layers of the primary sensory cortex.

Sensory systems are believed to play an important role in drug addiction, particularly in triggering craving and relapse, and it has been shown in previous studies that administration of cocaine can enhance evoked responses in the primary sensory cortex of experimental animals. Primary sensory cortex comprises a multi-layered structure to which a variety of roles have been assigned; an understanding of how cocaine affects evoked activity in these different layers may shed light on how drug-associated sensory cues gain control over behavior. The aim of the present study was to examine how cocaine affects whisker sensory responses in different layers of the primary sensory (barrel) cortex.