Ultracompact Multielectrode Array for Neurological Monitoring.

Patients with paralysis, spinal cord injury, or amputated limbs could benefit from using brain-machine interface technology for communication and neurorehabilitation. In this study, a 32-channel three-dimensional (3D) multielectrode probe array was developed for the neural interface system of a brain-machine interface to monitor neural activity. A novel microassembly technique involving lead transfer was used to prevent misalignment in the bonding plane during the orthogonal assembly of the 3D multielectrode probe array. Standard microassembly and biopackaging processes were utilized to implement the proposed lead transfer technique. The maximum profile of the integrated 3D neural device was set to 0.50 mm above the pia mater to reduce trauma to brain cells. Benchtop tests characterized the electrical impedance of the neural device. A characterization test revealed that the impedance of the 3D multielectrode probe array was on average approximately 0.55 MΩ at a frequency of 1 KHz. Moreover, in vitro cytotoxicity tests verified the biocompatibility of the device. Subsequently, 3D multielectrode probe arrays were implanted in rats and exhibited the capability to record local field potentials and spike signals.

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse.

Adaptation of the nervous system to different chemical and physiologic conditions is important for the homeostasis of brain processes and for learning and remembering appropriate responses to challenges. Although processes such as tolerance and dependence to various drugs of abuse have been known for a long time, it was recently discovered that even a single pharmacologically relevant dose of various drugs of abuse induces neuroplasticity in selected neuronal populations, such as the dopamine neurons of the ventral tegmental area, which persist long after the drug has been excreted. Prolonged (self-) administration of drugs induces gene expression, neurochemical, neurophysiological, and structural changes in many brain cell populations. These region-specific changes correlate with addiction, drug intake, and conditioned drugs effects, such as cue- or stress-induced reinstatement of drug seeking. In rodents, adolescent drug exposure often causes significantly more behavioral changes later in adulthood than a corresponding exposure in adults. Clinically the most impairing and devastating effects on the brain are produced by alcohol during fetal development. In adult recreational drug users or in medicated patients, it has been difficult to find persistent functional or behavioral changes, suggesting that heavy exposure to drugs of abuse is needed for neurotoxicity and for persistent emotional and cognitive alterations. This review describes recent advances in this important area of research, which harbors the aim of translating this knowledge to better treatments for addictions and related neuropsychiatric illnesses.

Priming locus coeruleus noradrenergic modulation of medial perforant path-dentate gyrus synaptic plasticity.

Priming phenomenon, in which an earlier exposure to a stimulus or condition alters synaptic plasticity in response to a subsequent stimulus or condition, known as a challenge, is an example of metaplasticity. In this review, we make the case that the locus coeruleus noradrenergic system-medial perforant path-dentate gyrus pathway is a neural ensemble amenable to studying priming-challenge effects on synaptic plasticity. Accumulating evidence points to a tyrosine hydroxylase-dependent priming effect achieved by pharmacological (nicotine and antipsychotics) or physiological (septal theta driving) manipulations of the locus coeruleus noradrenergic system that can facilitate noradrenaline-induced synaptic plasticity in the dentate gyrus of the hippocampus. The evidence suggests the hypothesis that behavioural experiences inducing tyrosine hydroxylase expression in the locus coeruleus may be sufficient to prime this form of metaplasticity. We propose exploring this phenomenon of priming and challenge physiologically, to determine whether behavioural experiences are sufficient to prime the locus coeruleus, enabling subsequent pharmacological or behavioural challenge conditions that increase locus coeruleus firing to release sufficient noradrenaline to induce long-lasting potentiation in the dentate gyrus. Such an approach may contribute to unravelling mechanisms underlying this form of metaplasticity and its importance in stress-related mnemonic processes.

Specific inhibition of p25/Cdk5 activity by the Cdk5 inhibitory peptide reduces neurodegeneration in vivo.

The aberrant hyperactivation of Cyclin-dependent kinase 5 (Cdk5), by the production of its truncated activator p25, results in the formation of hyperphosphorylated tau, neuroinflammation, amyloid deposition, and neuronal death in vitro and in vivo. Mechanistically, this occurs as a result of a neurotoxic insult that invokes the intracellular elevation of calcium to activate calpain, which cleaves the Cdk5 activator p35 into p25. It has been shown previously that the p25 transgenic mouse as a model to investigate the mechanistic implications of p25 production in the brain, which recapitulates deregulated Cdk5-mediated neuropathological changes, such as hyperphosphorylated tau and neuronal death. To date, strategies to inhibit Cdk5 activity have not been successful in targeting selectively aberrant activity without affecting normal Cdk5 activity. Here we show that the selective inhibition of p25/Cdk5 hyperactivation in vivo, through overexpression of the Cdk5 inhibitory peptide (CIP), rescues against the neurodegenerative pathologies caused by p25/Cdk5 hyperactivation without affecting normal neurodevelopment afforded by normal p35/Cdk5 activity. Tau and amyloid pathologies as well as neuroinflammation are significantly reduced in the CIP-p25 tetra transgenic mice, whereas brain atrophy and subsequent cognitive decline are reversed in these mice. The findings reported here represent an important breakthrough in elucidating approaches to selectively inhibit the p25/Cdk5 hyperactivation as a potential therapeutic target to reduce neurodegeneration.

Nicotine and clozapine cross-prime the locus coeruleus noradrenergic system to induce long-lasting potentiation in the rat hippocampus.

A priming-challenge schedule of nicotine treatment causes long-lasting potentiation (LLP), a form of synaptic plasticity closely associated with the norepinephrine (NE) neurotransmitter system, at the medial perforant path (MPP)-dentate gyrus (DG) synapse in the rat hippocampus. Previous reports revealed that nicotine activates the locus coeruleus (LC) noradrenergic (NAergic) system and this mechanism may underlie its beta-adrenoceptor sensitive LLP effects. Clozapine, an atypical antipsychotic, is also known to activate the LC. Interactions between nicotine and clozapine are of interest because of the prevalence of smoking in patients with schizophrenia and increasing interest in the use of nicotinic receptor ligands as cognitive enhancers. Rats were subchronically primed with nicotine, clozapine or saline. Twenty-one to twenty-eight days later, the effects of the nicotine, clozapine or saline challenge on the evoked field excitatory postsynaptic potentials (fEPSP) at the MPP-DG monosynaptic pathway were recorded as a measure of LLP. We confirmed the hypothesis that a challenge dose of either nicotine or clozapine induces LLP exclusively in nicotine- and clozapine-primed rats, and not in saline-primed rats, thus indicating a cross-priming effect. Moreover, unilateral suppression of LC using lidocaine abolished the LLP induced by nicotine in clozapine-primed rats. Furthermore, systemic treatment with clonidine (an α2 adrenoceptor agonist that reduces NAergic activity via autoreceptors) prior to the challenge doses blocked the nicotine/clozapine-induced LLP in nicotine- and clozapine-primed rats. These findings may add to understanding of the cognitive enhancing effects of nicotine.

Corticotropin-releasing factor infusion into nucleus incertus suppresses medial prefrontal cortical activity and hippocampo-medial prefrontal cortical long-term potentiation.

The medial prefrontal cortex (mPFC) in the rat has been implicated in a variety of cognitive processes, including working memory and expression of fear memory. We investigated the inputs from a brain stem nucleus, the nucleus incertus (NI), to the prelimbic area of the mPFC. This nucleus strongly expresses corticotropin-releasing factor type 1 (CRF1 ) receptors and responds to stress. A retrograde tracer was used to verify connections from the NI to the mPFC. Retrogradely labelled cells in the NI expressed CRF receptors. Electrophysiological manipulation of the NI revealed that stimulation of the NI inhibited spontaneous neuronal firing in the mPFC. Similarly, CRF infusion into the NI, in order to mimic a stressful condition, inhibited neuronal firing and burst firing in the mPFC. The effect of concurrent high-frequency stimulation of the NI on plasticity in the hippocampo-prelimbic medial prefrontal cortical (HP-mPFC) pathway was studied. It was found that electrical stimulation of the NI impaired long-term potentiation in the HP-mPFC pathway. Furthermore, CRF infusion into the NI produced similar results. These findings might account for some of the extra-pituitary functions of CRF and indicate that the NI may play a role in stress-driven modulation of working memory and possibly other cognitive processes subserved by the mPFC.

Depressant-like effects of parthenolide in a rodent behavioural antidepressant test battery.

The anti-serotonergic effects of parthenolide (PTL) demonstrated in platelets inspired the present psychopharmacological investigation, which employs a battery of rodent behavioural assays of depression. In mice, PTL (0.5-2 mg kg(-1)) exhibited dose-dependent depressant-like effects in a forced swim test and a tail suspension test, without affecting the baseline locomotor status. The doses (1 and 2 mg kg(-1)) that induced depressant-like effects were found to significantly reduce 5-hydroxytryptophan-induced head twitch response. Interaction studies revealed that the depressant-like effects of PTL (1 mg kg(-1)) were reversed more efficiently by serotonergic antidepressants (venlafaxine, escitalopram, citalopram, fluoxetine) than by others (desipramine, bupropion) tested. Chronic treatment of PTL (1 and 2 mg kg(-1)) augmented the hyper-emotionality of olfactory bulbectomized rats, when compared with sham rats, as observed in modified open field, elevated plus maze and social interaction paradigms. This study depicts the severe depressogenic potential of PTL (in its pure form) plausibly mediated by platelet/neuronal hypo-serotonergic effects.

OBscure but not OBsolete: Perturbations of the frontal cortex in common between rodent olfactory bulbectomy model and major depression.

Olfactory bulbectomy (OBX) has been used as a model of depression over several decades. This model presupposes a mechanism that is still not proven in clinical depression. A wealth of clinical literature has focused on the derangements in frontal cortex (prefrontal, orbitofrontal and anterior cingulate cortices) associated with depression. In this comprehensive review, anatomical, electrophysiological and molecular sequelae of bulbectomy in the rodent frontal cortex are explored and compared with findings on brains of humans with major depression. Certain commonalities in neurobiological features of the perturbed frontal cortex in the bulbectomised rodent and the depressed human brain are evident. Also, meta-analysis reports on clinical studies on depressed patients provide prima facie evidence that perturbations in the frontal cortex are associated with major depression. Analysing the pattern of perturbations in the chemical neuroanatomy of the frontal cortex will contribute to understanding of the neurobiology of depression. Revisiting the OBX model of depression to examine these neurobiological changes in frontal cortex with contemporary imaging, proteomics, lipidomics, metabolomics and epigenomics technologies is proposed as an approach to enhance the translational value of this animal model to facilitate identification of targets and biomarkers for clinical depression.

Ginsenoside Rg1 modulates medial prefrontal cortical firing and suppresses the hippocampo-medial prefrontal cortical long-term potentiation.

BACKGROUND: Panax ginseng is one of the most commonly used medicinal herbs worldwide for a variety of therapeutic properties including neurocognitive effects. Ginsenoside Rg1 is one of the most abundant active chemical constituents of this herb with known neuroprotective, anxiolytic, and cognition improving effects. METHODS: We investigated the effects of Rg1 on the medial prefrontal cortex (mPFC), a key brain region involved in cognition, information processing, working memory, and decision making. In this study, the effects of systemic administration of Rg1 (1 mg/kg, 3 mg/kg, or 10 mg/kg) on (1) spontaneous firing of the medial prefrontal cortical neurons and (2) long-term potentiation (LTP) in the hippocampal-medial prefrontal cortical (HP-mPFC) pathway were investigated in male Sprague-Dawley rats. RESULTS: The spontaneous neuronal activity of approximately 50% the recorded pyramidal cells in the mPFC was suppressed by Rg1. In addition, Rg1 attenuated LTP in the HP-mPFC pathway. These effects were not dose-dependent. CONCLUSION: This report suggests that acute treatment of Rg1 impairs LTP in the HP-mPFC pathway, perhaps by suppressing the firing of a subset of mPFC neurons that may contribute to the neurocognitive effects of Rg1.

Evaluation of anxiolytic potential of Celastrus oil in rat models of behaviour.

The Celastrus oil, extracted from seeds of Celastrus paniculatus tested at 2 dose levels (1 and 1.5 g/kg), exhibited significant anxiolytic activity and did not produce tolerance. The non-sedative nature and reversal of buspirone induced behaviour (in open field exploration) point to the serotonergic mechanism underlying the anxiolysis, inspiring further research.