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Pupil size covaries with the diffusion rate of the cholinergic and noradrenergic neurons throughout the brain, which are essential to arousal. Recent findings suggest slow pupil fluctuations during locomotion are an index of sustained activity in cholinergic axons, whereas phasic dilations are related to the activity of noradrenergic axons. Here we investigated arousal due to movement to actively control music (singing) and swaying to music, hypothesizing that actively engaging in musical behavior while singing and moving along to the music will more strongly engage participants emotionally and lead to a qualitatively different pattern of tonic and phasic pupil activity. A challenge in the analysis of pupil data is the turbulent behavior of pupil diameter due to exogenous ocular activity commonly encountered during motor tasks and the high variability typically found between individuals. To address this, we developed an algorithm that adaptively estimates and removes pupil responses to ocular events and a functional data methodology derived from Pfaffs' generalized arousal that provides a new statistical dimension in how pupil data can be interpreted according to putative neuromodulatory signaling. We found that actively engaging in singing enhanced slow cholinergic-related pupil dilations, and having the opportunity to move your body while performing amplified the effect of singing on pupil activity. Phasic pupil oscillations during motor execution attenuated in time, which often is interpreted as a measure of sense of agency over movement.

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

Pain transmission at the spinal cord is modulated by noradrenaline (NA)-mediated actions that arise from supraspinal areas. We studied the locus coeruleus (LC) to evaluate the expression of the cathecolamine-synthetizing enzyme tyrosine hydroxylase (TH) and search for local oxidative stress and possible consequences in descending pain modulation in a model of hydrocephalus, a disease characterized by enlargement of the cerebral ventricular system usually due to the obstruction of cerebrospinal fluid flow. Four weeks after kaolin injection into the cisterna magna, immunodetection of the catecholamine-synthetizing enzymes TH and dopamine-β-hydroxylase (DBH) was performed in the LC and spinal cord. Colocalization of the oxidative stress marker 8-OHdG (8-hydroxyguanosine; 8-OHdG), with TH in the LC was performed. Formalin was injected in the hindpaw both for behavioral nociceptive evaluation and the immunodetection of Fos expression in the spinal cord. Hydrocephalic rats presented with a higher expression of TH at the LC, of TH and DBH at the spinal dorsal horn along with decreased nociceptive behavioral responses in the second (inflammatory) phase of the formalin test, and formalin-evoked Fos expression at the spinal dorsal horn. The expression of 8-OHdG was increased in the LC neurons, with higher co-localization in TH-immunoreactive neurons. Collectively, the results indicate increased noradrenergic expression at the LC during hydrocephalus. The strong oxidative stress damage at the LC neurons may lead to local neuroprotective-mediated increases in NA levels. The increased expression of catecholamine-synthetizing enzymes along with the decreased nociception-induced neuronal activation of dorsal horn neurons and behavioral pain signs may indicate that hydrocephalus is associated with alterations in descending pain modulation.

This study investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) enhances reversal learning and augments noradrenergic biomarkers (i.e., pupil size, cortisol, and salivary alpha-amylase [sAA]). We also explored the effect of taVNS on respiratory rate and cardiac vagal activity (CVA). Seventy-one participants received stimulation of either the cymba concha (taVNS) or the earlobe (sham) of the left ear. After learning a series of cue-outcome associations, the stimulation was applied before and throughout a reversal phase in which cue-outcome associations were changed for some (reversal), but not for other (distractor) cues. Tonic pupil size, salivary cortisol, sAA, respiratory rate, and CVA were assessed at different time points. Contrary to our hypothesis, taVNS was not associated with an overall improvement in performance on the reversal task. Compared to sham, the taVNS group performed worse for distractor than reversal cues. taVNS did not increase tonic pupil size and sAA. Only post hoc analyses indicated that the cortisol decline was steeper in the sham compared to the taVNS group. Exploratory analyses showed that taVNS decreased respiratory rate but did not affect CVA. The weak and unexpected effects found in this study might relate to the lack of parameters optimization for taVNS and invite to further investigate the effect of taVNS on cortisol and respiratory rate. ispartof: Psychophysiology vol:58 issue:10 pages:1-20 ispartof: location:United States status: published

Fear extinction is the well-known process of fear reduction through repeated re-exposure to a feared stimulus without the aversive outcome. The last two decades have witnessed a surge of interest in extinction learning. First, extinction learning is observed across species, and especially research on rodents has made great strides in characterising the physical substrate underlying extinction learning. Second, extinction learning is considered of great clinical significance since it constitutes a crucial component of exposure treatment. While effective in reducing fear responding in the short term, extinction learning can lose its grip, resulting in a return of fear (i.e., laboratory model for relapse of anxiety symptoms in patients). Optimization of extinction learning is, therefore, the subject of intense investigation. It is thought that the success of extinction learning is, at least partly, determined by the mismatch between what is expected and what actually happens (prediction error). However, while much of our knowledge about the neural circuitry of extinction learning and factors that contribute to successful extinction learning comes from animal models, translating these findings to humans has been challenging for a number of reasons. Here, we present an overview of what is known about the animal circuitry underlying extinction of fear, and the role of prediction error. In addition, we conducted a systematic literature search to evaluate the degree to which state-of-the-art neuroimaging methods have contributed to translating these findings to humans. Results show substantial overlap between networks in animals and humans at a macroscale, but current imaging techniques preclude comparisons at a smaller scale, especially in sub-cortical areas that are functionally heterogeneous. Moreover, human neuroimaging shows the involvement of numerous areas that are not typically studied in animals. Results obtained in research aimed to map the extinction circuit are largely dependent on the methods employed, not only across species, but also across human neuroimaging studies. Directions for future research are discussed. ispartof: NEUROBIOLOGY OF LEARNING AND MEMORY vol:155 pages:113-126 ispartof: location:United States status: published

The neocortex is densely innervated by basal forebrain (BF) cholinergic neurons. Long-range axons of cholinergic neurons regulate higher-order cognitive function and dysfunction in the neocortex by releasing acetylcholine (ACh). ACh release dynamically reconfigures neocortical microcircuitry through differential spatiotemporal actions on cell-types and their synaptic connections. At the cellular level, ACh release controls neuronal excitability and firing rate, by hyperpolarizing or depolarizing target neurons. At the synaptic level, ACh impacts transmission dynamics not only by altering the presynaptic probability of release, but also the magnitude of the postsynaptic response. Despite the crucial role of ACh release in physiology and pathophysiology, a comprehensive understanding of the way it regulates the activity of diverse neocortical cell-types and synaptic connections has remained elusive. This review aims to summarize the state-of-the-art anatomical and physiological data to develop a functional map of the cellular, synaptic and microcircuit effects of ACh in the neocortex of rodents and non-human primates, and to serve as a quantitative reference for those intending to build data-driven computational models on the role of ACh in governing brain states.

Adaptation to the ever-changing world is critical for survival, and our brains are particularly tuned to remember events that differ from previous experiences. Novel experiences induce dopamine release in the hippocampus, a process which promotes memory persistence. While axons from the ventral tegmental area (VTA) were generally thought to be the exclusive source of hippocampal dopamine, recent studies have demonstrated that noradrenergic neurons in the locus coeruleus (LC) corelease noradrenaline and dopamine in the hippocampus and that their dopamine release boosts memory retention as well. In this opinion article, we propose that the projections originating from the VTA and the LC belong to two distinct systems that enhance memory of novel events. Novel experiences that share some commonality with past ones (‘common novelty’) activate the VTA and promote semantic memory formation via systems memory consolidation. By contrast, experiences that bear only a minimal relationship to past experiences (‘distinct novelty’) activate the LC to trigger strong initial memory consolidation in the hippocampus, resulting in vivid and long-lasting episodic memories., Highlights Novelty induces dopamine release in the hippocampus, triggering memory consolidation to boost memory persistence. Two dopaminergic systems (the ventral tegmental area- and locus coeruleus-hippocampus systems) can stabilise memory through novelty-induced dopamine release in the hippocampus. Novel experiences can be viewed as a spectrum, from experiences that, while clearly novel, share some commonality with past experiences (‘common novelty’), to more fundamentally distinct experiences that bear minimal relationships to past experiences (‘distinct novelty’). We propose that events characterised by ‘common novelty’ boost memory retention via activation of the ventral tegmental area-hippocampus system, resulting in initial consolidation followed by systems consolidation to create neocortical, semantic, long-term memories. We further propose that events characterised by ‘distinct novelty’ lead to the boost of detailed hippocampal, episodic, long-term memory via activation of the locus coeruleus-hippocampus system through strong upregulation of the synaptic tagging and capture mechanism.

The locus coeruleus (LC) plays a crucial role in modulating several higher order cognitive functions via its widespread projections to the entire brain. We set out to investigate the hypothesis that LC functional connectivity (FC) may fluctuate nonlinearly with age and explored its relation to memory function. To that end, 49 cognitively healthy individuals (19-74 years) underwent ultra high-resolution 7T resting-state functional magnetic resonance imaging and cognitive testing. FC patterns from the LC to regions of the isodendritic core network and cortical regions were examined using region of interest-to-region of interest analyses. Curvilinear patterns with age were observed for FC between the left LC and cortical regions and the nucleus basalis of Meynert. A linear negative association was observed between age and LC-FC and ventral tegmental area. Higher levels of FC between the LC and nucleus basalis of Meynert or ventral tegmental area were associated with lower memory performance from age of 40 years onward. Thus, different LC-FC patterns early in life can signal subtle memory deficits. Furthermore, these results highlight the importance of intact interactions between neurotransmitter systems for optimal cognitive aging.

The dorsolateral prefrontal cortex (dlPFC), which is regarded as the primary site for visuospatial working memory in the brain, is significantly modulated by dopamine (DA) and norepinephrine (NE). DA and NE originate in the ventral tegmental area (VTA) and locus coeruleus (LC), respectively, and have been shown to have an ‘inverted-U’ dose-response profile in dlPFC, where the level of arousal and decision-making performance is a function of DA and NE concentrations. Moreover, there appears to be a sweet spot, in terms of the level of DA and NE activation, which allows for optimal working memory and behavioral performance. When either DA or NE is too high, input to the PFC is essentially blocked. When either DA or NE is too low, PFC network dynamics become noisy and activity levels diminish. Mechanisms for how this is occurring have been suggested, however, they have not been tested in a large-scale model with neurobiologically plausible network dynamics. Also, DA and NE levels have not been simultaneously manipulated experimentally, which is not realistic in vivo due to strong bi-directional connections between the VTA and LC. To address these issues, we built a spiking neural network model that includes D1, α2A, and α1 receptors. The model was able to match the inverted-U profiles that have been shown experimentally for differing levels of DA and NE. Furthermore, we were able to make predictions about what working memory and behavioral deficits may occur during simultaneous manipulation of DA and NE outside of their optimal levels. Specifically, when DA levels were low and NE levels were high, cues could not be held in working memory due to increased noise. On the other hand, when DA levels were high and NE levels were low, incorrect decisions were made due to weak overall network activity. We also show that lateral inhibition in working memory may play a more important role in increasing signal-to-noise ratio than increasing recurrent excitatory input

Made available in DSpace on 2013-08-28T14:13:42Z (GMT). No. of bitstreams: 1 WOS000305800800001.pdf: 2761758 bytes, checksum: 201c6a88a896ef2a2d8590dec0969178 (MD5) Made available in DSpace on 2013-09-30T19:23:21Z (GMT). No. of bitstreams: 2 WOS000305800800001.pdf: 2761758 bytes, checksum: 201c6a88a896ef2a2d8590dec0969178 (MD5) WOS000305800800001.pdf.txt: 69129 bytes, checksum: 22565180d285030e432331c7e3fbecc0 (MD5) Previous issue date: 2012-06-28 Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-20T15:34:09Z No. of bitstreams: 2 WOS000305800800001.pdf: 2761758 bytes, checksum: 201c6a88a896ef2a2d8590dec0969178 (MD5) WOS000305800800001.pdf.txt: 69129 bytes, checksum: 22565180d285030e432331c7e3fbecc0 (MD5) Made available in DSpace on 2014-05-20T15:34:09Z (GMT). No. of bitstreams: 2 WOS000305800800001.pdf: 2761758 bytes, checksum: 201c6a88a896ef2a2d8590dec0969178 (MD5) WOS000305800800001.pdf.txt: 69129 bytes, checksum: 22565180d285030e432331c7e3fbecc0 (MD5) Previous issue date: 2012-06-28 Spanish Ministry of Science and Innovation (MICINN) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) AUIP (Programa de Becas de Movilidad Academica) The inferior colliculus (IC) and the locus coeruleus (LC) are two midbrain nuclei that integrate multimodal information and play a major role in novelty detection to elicit an orienting response. Despite the reciprocal connections between these two structures, the projection pattern and target areas of the LC within the subdivisions of the rat IC are still unknown. Here, we used tract-tracing approaches combined with immunohistochemistry, densitometry, and confocal microscopy (CM) analysis to describe a projection from the LC to the IC. Biotinylated dextran amine (BDA) injections into the LC showed that the LC-IC projection is mainly ipsilateral (90%) and reaches, to a major extent, the dorsal and lateral part of the IC and the intercollicular commissure. Additionally, some LC fibers extend into the central nucleus of the IC. The neurochemical nature of this projection is noradrenergic, given that tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DBH) colocalize with the BDA-Iabeled fibers from the LC. To determine the total field of the LC innervations in the IC, we destroyed the LC neurons and fibers using a highly selective neurotoxin, DSP-4, and then studied the distribution and density of TH- and DBH-immunolabeled axons in the IC. In the DSP-4 treated animals, the number of axonal fibers immunolabeled for TH and DBH were deeply decreased throughout the entire rostrocaudal extent of the IC and its subdivisions compared to controls. Our densitometry results showed that the IC receives up to 97% of its noradrenergic innervations from the LC neurons and only 3% from non-coeruleus neurons. Our results also indicate that TH immunoreactivity in the IC was less impaired than the immunoreactivity for DBH after DSP-4 administration. This is consistent with the existence of an important dopaminergic projection from the substantia nigra to the IC. In conclusion, our study demonstrates and quantifies the noradrenergic projection from the LC to the IC and its subdivisions. The re-examination of the TH and DBH immunoreactivity after DSP-4 treatment provides insights into the source, extent, and topographic distribution of the LC efferent network in the IC, and hence, contributes to our understanding of the role of the noradrenaline (NA) system in auditory processing. Univ Salamanca, INCYL, Salamanca 37007, Spain Univ Salamanca, Inst Biomed Res Salamanca, Salamanca 37007, Spain São Paulo State Univ UNESP, Biosci Inst, São Paulo, Brazil Univ Salamanca, Dept Cellular Biol & Pathol, Salamanca 37007, Spain São Paulo State Univ UNESP, Biosci Inst, São Paulo, Brazil MICINN: BFU2010-17754 FAPESP: 08/02771-6

domains and show early synaptic responses to glutamate before the establishment of synaptic connections with mitral cells at the more distal portions of their dendritic arbors ( Panzanelli et al., 2009 ). In addition, olfactory deprivation differentially affects spine density in the distal and proximal den-dritic domains, where respectively centrip-etal and centrifugal synaptic connections take place (Kelsch et al., 2009). Hence, the role of central brain activity is exceedingly likely to affect the fate of developing GCs, but the mechanisms of this effect have yet to be elucidated. Surprisingly, only a few reports have aimed to do so (Bauer et al., 2003; Cooper-Kuhn et al., 2004; Veyrac et al., 2005, 2009) and, although focusing on the local OB reveals why younger neurons may be preferable to older ones, the mecha-nisms by which the brain makes this choice can not be fully clarified without consider -ing its feedback modulatory activity.Moreno et al. (2012) have recently shed new light on this issue and analyzed the interaction between centrifugal innerva-tion and plasticity in the olfactory bulb in a sensory context meaningful for both. The authors investigated the involvement of the noradrenergic signaling in the olfac-tory perceptual learning, a form of learning in which previous experience like olfactory habituation allows discrimination between perceptually similar odorants.They showed that blocking the noradr-energic system during olfactory enrichment abolishes its positive effects on olfactory dis-criminatory ability while the stimulation of the noradrenergic system alone results in better performances in the discriminatory task. To complete the picture of the involve-ment of the noradrenergic system, they

1. The effects of microstimulation of the locus coeruleus (LC) region on the spontaneous discharge and the response of SI neurons to natural and electrical stimulation of the skin have been investigated in 26 urethane anesthetized Sprague-Dawley rats. In particular, one or two air puffs, 5-10 msec in duration, 1-2 psi, usually separated by an interval of 40 msec, were applied on the hairy skin of the wrist or the forepaw at the presentation rate of 1/sec. For units unresponsive to air puffs, similar presentation of low intensity electrical stimuli (0.2-5.0 V, 0.2-0.4 msec pulses) were applied through two needles inserted on the most effective area of the skin. Both natural and electrical stimulations of the skin were applied under control conditions, as well as 50 msec after a 250 msec train of 0.3 msec pulses at 40 Hz. 20-30 microA applied stereotaxically to the LC complex through a tungsten microelectrode. 2. Not all cortical units exhibited spontaneous discharge. Most of the units, however, which were spontaneously active, were inhibited by electrical stimulation of the LC complex, while the remaining ones were excited. The sites of stimulation, which included either the LC proper or the locus subcoeruleus, were identified following both anatomical and physiological criteria. 3. SI neurons recorded at sites between 400 and 950 microns below the surface of the cortex, thus being most likely granule cells of layers III and IV, responded to cutaneous stimuli with spikes which occurred with a latency of 20-30 msec in response to single air puffs and a latency of 15-20 msec in response to single electrical pulses to the skin. In both instances the response to the second stimulus applied at the interstimulus interval of 40 msec was markedly reduced or abolished due to postexcitatory inhibition following the response to the first stimulus (in-field inhibition). In contrast, units particularly located at or below 1000 microns from the cortical surface, which were of very large size probably corresponding to large layer V pyramidal cells, were often difficult to activate with air puffs applied at the centre of the receptive field (RF) and were submitted to electrical stimulation of the skin. 4. Among the 59 isolated SI units tested either to air puffs (45 neurons) or to electrical skin stimulation (14 neurons), 15 units (i.e., 25.4%) were facilitated, while 12 units (i.e., 20.3%) were inhibited following stimulation of the LC complex. 5. A marked feature of the facilitatory effects which usually involved the predominant response to the first air puff, but also the smaller response to the second puff, was that the increase in the number of spikes per stimulus was accompanied by a temporal focusing of the responses characterized by a clear tightening of the latency and narrowing of the peak of activity, which was often accompanied by some level of tonic inhibition of the background discharge. Thus, LC stimulation increased the signal-to-noise ratio of SI neuronal responses to skin stimulation. When inhibitory effects were induced by LC stimulation, they clearly affected the unit response to the first air puff, which was severely depressed. However, the response to the second puff could be facilitated, suggesting that LC stimulation might have produced inhibition of those inhibitory interneurons responsible for the postexcitatory inhibition of the units under examination. Evidence for spatial focusing of the response was not easily documented. In some units, however, LC stimulation produced either facilitation of the responses to puffs at the receptive field center and inhibition of the responses to puffs at the edge at the receptive field or vice versa. 6. Since the LC complex contains in the rat a predominant population of noradrenergic neurons, it is likely that the effects described above were mainly due to activation of these noradrenergic neurons. 7. (ABSTRACT TRUNCATED)