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Highlights: [•] Actin cytoskeleton and its regulatory proteins are needed for memory formation. [•] Actin cytoskeleton and its regulatory proteins are essential for synaptic plasticity. [•] Actin cytoskeleton is involved in synaptic transmission and neuronal morphogenesis. [ABSTRACT FROM AUTHOR]

Highlights: [•] Can animal models be used for studying affective and cognitive comorbidities of pain? [•] How does pain interact with its comorbidities in the animals? [•] What are the underlying mechanisms of pain comorbidities in the animals? [Copyright &y& Elsevier]

Highlights: [•] Excitotoxicity is a primary mechanism of neuronal injury following stroke. [•] Excitotoxicity requires influx of calcium ion through the NMDA receptor. [•] Different subpopulations of the NMDA receptor elicit distinct functional output. [•] NMDA receptor promotes neuronal death or survival depending on what's downstream. [•] Studying downstream signaling events allows development of better stroke treatments. [ABSTRACT FROM AUTHOR]

Highlights: [•] Obesity originates from disturbed neuropsychological functioning. [•] Chronic stress enhances food intake and lowers cerebral energy content. [•] Food intake and stress per se activate the reward circuitry. [•] Stress, neuroenergetic depletion, and reward system activation build a vicious cycle. [•] This vicious cycle induces obesity. [Copyright &y& Elsevier]

Highlights: [•] Hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels are involved in multiple physiological processes. [•] HCN channels are excellent targets of various cellular signals to finely regulate neuronal responses to external stimuli. [•] Dysregulation of HCN channels is involved in a variety of neurological disorders. [ABSTRACT FROM AUTHOR]

The brain renin–angiotensin system (RAS) has long been known to regulate several classic physiologies including blood pressure, sodium and water balance, cyclicity of reproductive hormones and sexual behaviors, and pituitary gland hormones. These physiologies are thought to be under the control of the angiotensin II (AngII)/AT1 receptor subtype system. The AT2 receptor subtype is expressed during fetal development and is less abundant in the adult. This receptor appears to oppose growth responses facilitated by the AT1 receptor, as well as growth factor receptors. Recent evidence points to an important contribution by the brain RAS to non-classic physiologies mediated by the newly discovered angiotensin IV (AngIV)/AT4 receptor subtype system. These physiologies include the regulation of blood flow, modulation of exploratory behavior, and a facilitory role in learning and memory acquisition. This system appears to interact with brain matrix metalloproteinases in order to modify extracellular matrix molecules thus permitting the synaptic remodeling critical to the neural plasticity presumed to underlie memory consolidation, reconsolidation, and retrieval. There is support for an inhibitory influence by AngII activation of the AT1 subtype, and a facilitory role by AngIV activation of the AT4 subtype, on neuronal firing rate, long-term potentiation, associative and spatial learning. The discovery of the AT4 receptor subtype, and its facilitory influence upon learning and memory, suggest an important role for the brain RAS in normal cognitive processing and perhaps in the treatment of dysfunctional memory disease states. [Copyright &y& Elsevier]

The cellular and the inter-connective complexity of the central nervous system (CNS) necessitate’s analysis of functioning at both the system and single cell levels. Systems neuroscience has developed procedures that facilitate the analysis of multicellular systems including multielectrode arrays, dye tracings and lesioning assays, and at the single cell level there have been significant strides in assessing the physiology and morphology of individual cells. Until recently little progress had been made in understanding the molecular biology of single neuronal cells. This review will highlight the development of PCR and aRNA procedures for analysis of mRNA abundances in single cells. Also, other procedures for the analysis of protein abundances as well as the association of RNA with proteins will also be summarized. These procedures promise to provide experimental insights that will help unravel the functional mechanisms regulating the cellular components of the CNS. [Copyright &y& Elsevier]

Protein kinases critically regulate synaptic plasticity in the mammalian hippocampus. Cyclic-AMP dependent protein kinase (PKA) is a serine–threonine kinase that has been strongly implicated in the expression of specific forms of long-term potentiation (LTP), long-term depression (LTD), and hippocampal long-term memory. We review the roles of PKA in activity-dependent forms of hippocampal synaptic plasticity by highlighting particular themes that have emerged in ongoing research. These include the participation of distinct isoforms of PKA in specific types of synaptic plasticity, modification of the PKA-dependence of LTP by multiple factors such as distinct patterns of imposed activity, environmental enrichment, and genetic manipulation of signalling molecules, and presynaptic versus postsynaptic mechanisms for PKA-dependent LTP. We also discuss many of the substrates that have been implicated as targets for PKA’s actions in hippocampal synaptic plasticity, including CREB, protein phosphatases, and glutamatergic receptors. Future prospects for shedding light on the roles of PKA are also described from the perspective of specific aspects of synaptic physiology and brain function that are ripe for investigation using incisive genetic, cell biological, and electrophysiological approaches. [Copyright &y& Elsevier]

Amyloid-β precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. It is the source of the amyloid-β (Aβ) peptide found in neuritic plaques of Alzheimer’s disease (AD) patients. Because Aβ shows neurotoxic properties, and because familial forms of AD promote Aβ accumulation, a massive international research effort has been aimed at understanding the mechanisms of Aβ generation, catabolism and toxicity. APP, however, is an extremely complex molecule that may be a functionally important molecule in its full-length configuration, as well as being the source of numerous fragments with varying effects on neural function. For example, one fragment derived from the non-amyloidogenic processing pathway, secreted APPα (sAPPα), is neuroprotective, neurotrophic and regulates cell excitability and synaptic plasticity, while Aβ appears to exert opposing effects. Less is known about the neural functions of other fragments, but there is a growing interest in understanding the basic biology of APP as it has become recognized that alterations in the functional activity of the APP fragments during disease states will have complex effects on cell function. Indeed, it has been proposed that reductions in the level or activity of certain APP fragments, in addition to accumulation of Aβ, may play a critical role in the cognitive dysfunction associated with AD, particularly early in the course of the disease. To test and modify this hypothesis, it is important to understand the roles that full-length APP and its fragments normally play in neuronal structure and function. Here we review evidence addressing these fundamental questions, paying particular attention to the contributions that APP fragments play in synaptic transmission and neural plasticity, as these may be key to understanding their effects on learning and memory. It is clear from this literature that APP fragments, including Aβ, can exert a powerful regulation of key neural functions including cell excitability, synaptic transmission and long-term potentiation, both acutely and over the long-term. Furthermore, there is a small but growing literature confirming that these fragments correspondingly regulate behavioral learning and memory. These data indicate that a full account of cognitive dysfunction in AD will need to incorporate the actions of the full complement of APP fragments. To this end, there is an urgent need for a dedicated research effort aimed at understanding the behavioral consequences of altered levels and activity of the different APP fragments as a result of experience and disease. [Copyright &y& Elsevier]

Ca2+-induced Ca2+ release (CICR) mediated by sarcoplasmic reticulum resident ryanodine receptors (RyRs) has been well described in cardiac, skeletal and smooth muscle. In brain, RyRs are localised primarily to endoplasmic reticulum (ER) and have been demonstrated in postsynaptic entities, astrocytes and oligodendrocytes where they regulate intracellular Ca2+ concentration ([Ca2+]i), membrane potential and the activity of a variety of second messenger systems. Recently, the contribution of presynaptic RyRs and CICR to functions of central and peripheral presynaptic terminals, including neurotransmitter release, has received increased attention. However, there is no general agreement that RyRs are localised to presynaptic terminals, nor is it clear that RyRs regulate a large enough pool of intracellular Ca2+ to be physiologically significant. Here, we review direct and indirect evidence that on balance favours the notion that ER and RyRs are found in presynaptic terminals and are physiologically significant. In so doing, it became obvious that some of the controversy originates from issues related to (i) the ability to demonstrate conclusively the physical presence of ER and RyRs, (ii) whether the biophysical properties of RyRs are such that they can contribute physiologically to regulation of presynaptic [Ca2+]i, (iii) how ER Ca2+ load and feedback gain of CICR contributes to the ability to detect functionally relevant RyRs, (iv) the distance that Ca2+ diffuses from plasma membranes to RyRs to trigger CICR and from RyRs to the Active Zone to enhance vesicle release, and (v) the experimental conditions used. The recognition that ER Ca2+ stores are able to modulate local Ca2+ levels and neurotransmitter release in presynaptic terminals will aid in the understanding of the cellular mechanisms controlling neuronal function. [Copyright &y& Elsevier]

It is only recently that a number of studies on synaptic plasticity in the hippocampus and other brain areas have considered that a heterosynaptic modulatory input could be recruited as well as the coincident firing of pre- and post-synaptic neurons. So far, the strongest evidence for such a regulation has been attributed to dopaminergic (DA) systems but other modulatory pathways have also been considered to influence synaptic plasticity. This review will focus on dopamine contribution to synaptic plasticity in different brain areas (hippocampus, striatum and prefrontal cortex) with, for each region, a few lines on the distribution of DA projections and receptors. New insights into the possible mechanisms underlying these plastic changes will be considered. The contribution of various DA systems in certain forms of learning and memory will be reviewed with recent advances supporting the hypothesis of similar cellular mechanisms underlying DA regulation of synaptic plasticity and memory processes in which the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway has a potential role. To summarize, endogenous DA, which depends on the activity patterns of DA midbrain neurons in freely moving animals, appears as a key regulator in specific synaptic changes observed at certain stages of learning and memory and of synaptic plasticity. [Copyright &y& Elsevier]

The hypothesis that sleep promotes learning and memory has long been a subject of active investigation. This hypothesis implies that sleep must facilitate synaptic plasticity in some way, and recent studies have provided evidence for such a function. Our knowledge of both the cellular neurophysiology of sleep states and of the cellular and molecular mechanisms underlying synaptic plasticity has expanded considerably in recent years. In this article, we review findings in these areas and discuss possible mechanisms whereby the neurophysiological processes characteristic of sleep states may serve to facilitate synaptic plasticity. We address this issue first on the cellular level, considering how activation of T-type Ca2+ channels in nonREM sleep may promote either long-term depression or long-term potentiation, as well as how cellular events of REM sleep may influence these processes. We then consider how synchronization of neuronal activity in thalamocortical and hippocampal–neocortical networks in nonREM sleep and REM sleep could promote differential strengthening of synapses according to the degree to which activity in one neuron is synchronized with activity in other neurons in the network. Rather than advocating one specific cellular hypothesis, we have intentionally taken a broad approach, describing a range of possible mechanisms whereby sleep may facilitate synaptic plasticity on the cellular and/or network levels. We have also provided a general review of evidence for and against the hypothesis that sleep does indeed facilitate learning, memory, and synaptic plasticity. [Copyright &y& Elsevier]