Normal-to-cancer (NTC) transition is known to be closely associated to cell´s biomechanical properties which are dependent on the dynamics of the intracellular medium. This study probes different ...human cancer cells (breast, prostate and lung), concomitantly to their healthy counterparts, aiming at characterising the dynamical profile of water in distinct cellular locations, for each type of cell, and how it changes between normal and cancer states. An increased plasticity of the cytomatrix is observed upon normal-to-malignant transformation, the lung carcinoma cells displaying the highest flexibility followed by prostate and breast cancers. Also, lung cells show a distinct behaviour relative to breast and prostate, with a higher influence from hydration water motions and localised fast rotations upon NTC transformation. Quasielastic neutron scattering techniques allowed to accurately distinguish the different dynamical processes taking place within these highly heterogeneous cellular systems. The results thus obtained suggest that intracellular water dynamics may be regarded as a specific reporter of the cellular conditions-either healthy or malignant.
► This paper describes the animal models chosen with regards to assessing the construct of control of attention by the CNTRICS II meeting. ► These are the 5-choice serial reaction time, 5-choice ...continuous performance, and the distractor condition sustained attention tasks. ► Each was judged to have high construct validity; the paper describes current findings and needed areas of development. ► Recommendations are also made for better preclinical task development in any cognitive domain.
Schizophrenia is associated with impaired attention. The top-down control of attention, defined as the ability to guide and refocus attention in accordance with internal goals and representations, was identified by the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative as an important construct for task development and research. A recent CNTRICS meeting identified three tasks commonly used with rodent models as having high construct validity and promise for further development: The 5-choice serial reaction time task, the 5-choice continuous performance task, and the distractor condition sustained attention task. Here we describe their current status, including data on their neural substrates, evidence for sensitivity to neuropharmacological manipulations and genetic influences, and data from animal models of the cognitive deficits of schizophrenia. A common strength is the development of parallel human tasks to facilitate connections to the neural circuitry and drug development research done in these animal models. We conclude with recommendations for the steps needed to improve testing so that it better represents the complex biological and behavioral picture presented by schizophrenia.
Basal forebrain corticopetal neurons participate in the mediation of arousal, specific attentional functions and rapid eye movement sleep-associated dreaming. Recent studies on the afferent ...regulation of basal forebrain neurons by telencephalic and brainstem inputs have provided the basis for hypotheses which, collectively, propose that the involvement of basal forebrain corticopetal projections in arousal, attention and dreaming can be dissociated on the basis of their regulation via major afferent projections. While the processing underlying sustained, selective and divided attention performance depends on the integrity of the telencephalic afferent regulation of basal forebrain corticopetal neurons, arousal-induced attentional processing (i.e. stimulus detection, selection and processing as a result of a novel, highly salient, aversive or incentive stimuli) is mediated via the ability of brainstem ascending noradrenergic projections to the basal forebrain to activate or “recruit” these telencephalic afferent circuits of the basal forebrain. In rapid eye movement sleep, both the basal forebrain and thalamic cortiocopetal projections are stimulated by cholinergic afferents originating mainly from the pedunculopontine and laterodorsal tegmenta in the brainstem. Rapid eye movement sleep-associated dreaming is described as a form of hyperattentional processing, mediated by increased activity of cortical cholinergic inputs and their cortical interactions with activated thalamic efferents. In this context, long-standing speculations about the similarities between dreaming and psychotic cognition are substantiated by describing the role of an over(re)active cortical cholinergic input system in either condition.
Finally, while determination of the afferent regulation of basal forebrain corticopetal neurons in different behavioral/cognitive states assists in defining the general cognitive functions of cortical acetylcholine, this research requires a specification of the precise anatomical organization of basal forebrain afferents and their interactions in the basal forebrain. Furthermore, the present hypotheses remain incomplete because of the paucity of data concerning the regulation and role of basal forebrain non-cholinergic, particularly GABAergic, efferents.
Sustaining and recovering attentional performance requires interactions between the brain's motivation and attention systems. The first experiment demonstrated that in rats performing a sustained ...attention task (SAT), presentation of a distractor (dSAT) augmented performance-associated increases in cholinergic neurotransmission in prefrontal cortex. Because stimulation of NMDA receptors in the shell of the nucleus accumbens activates PFC cholinergic neurotransmission, a second experiment demonstrated that bilateral infusions of NMDA into the NAc shell, but not core, improved dSAT performance to levels observed in the absence of a distractor. A third experiment demonstrated that removal of prefrontal or posterior parietal cholinergic inputs, by intracortical infusions of the cholinotoxin 192 IgG-saporin, attenuated the beneficial effects of NMDA on dSAT performance. Mesolimbic activation of cholinergic projections to the cortex benefits the cognitive control of attentional performance by enhancing the detection of cues and the filtering of distractors.
Water dynamics in human cancer and non-cancer tissues Marques, M. P. M; Santos, I. P; Batista de Carvalho, A. L. M ...
Physical chemistry chemical physics : PCCP,
06/2022, Letnik:
24, Številka:
25
Journal Article
Recenzirano
Normal-to-malignant transformation is a poorly understood process associated with cellular biomechanical properties. These are strongly dependent on the dynamical behaviour of water, known to play a ...fundamental role in normal cellular activity and in the maintenance of the three-dimensional architecture of the tissue and the functional state of biopolymers. In this study, quasi-elastic neutron scattering was used to probe the dynamical behaviour of water in human cancer specimens and their respective surrounding normal tissue from breast and tongue, as an innovative approach for identifying particular features of malignancy. This methodology has been successfully used by the authors in human cells and was the first study of human tissues by neutron scattering techniques. A larger flexibility was observed for breast
versus
tongue tissues. Additionally, different dynamics were found for malignant and non-malignant specimens, depending on the tissue: higher plasticity for breast invasive cancer
versus
the normal, and an opposite effect for tongue. The data were interpreted in the light of two different water populations within the samples: one displaying bulk-like dynamics (extracellular and intracellular/cytoplasmic) and another with constrained flexibility (extracellular/interstitial and intracellular/hydration layers).
Normal-to-malignant transformation is a poorly understood process associated with cellular biomechanical properties.
The hypothesis that cortical cholinergic inputs mediate attentional functions and capacities has been extensively substantiated by experiments assessing the attentional effects of specific ...cholinotoxic lesions of cortical cholinergic inputs, attentional performance-associated cortical acetylcholine release, and the effects of pharmacological manipulations of the excitability of basal forebrain corticopetal cholinergic projections on attentional performance. At the same time, numerous animal experiments have suggested that the integrity of cortical cholinergic inputs is not necessary for learning and memory, and a dissociation between the role of the cortical cholinergic input system in attentional functions and in learning and memory has been proposed. We speculate that this dissociation is due, at least in part, to the use of standard animal behavioral tests for the assessment of learning and memory which do not sufficiently tax defined attentional functions. Attentional processes and the allocation of attentional capacities would be expected to influence the efficacy of the acquisition and recall of declarative information and therefore, persistent abnormalities in the regulation of the cortical cholinergic input system may yield escalating impairments in learning and memory. Furthermore, the cognitive effects of loss of cortical cholinergic inputs are augmented by the disruption of the top–down regulation of attentional functions that normally acts to optimize information processing in posterior cortical areas. Because cortical cholinergic inputs play an integral role in the mediation of attentional processing, the activity of cortical cholinergic inputs is hypothesized to also determine the efficacy of learning and memory.
The capacity of the high‐affinity choline transporter (CHT) to import choline into presynaptic terminals is essential for acetylcholine synthesis. Ceramic‐based microelectrodes, coated at recording ...sites with choline oxidase to detect extracellular choline concentration changes, were attached to multibarrel glass micropipettes and implanted into the rat frontoparietal cortex. Pressure ejections of hemicholinium‐3 (HC‐3), a selective CHT blocker, dose‐dependently reduced the uptake rate of exogenous choline as well as that of choline generated in response to terminal depolarization. Following the removal of CHTs, choline signal recordings confirmed that the demonstration of potassium‐induced choline signals and HC‐3‐induced decreases in choline clearance require the presence of cholinergic terminals. The results obtained from lesioned animals also confirmed the selectivity of the effects of HC‐3 on choline clearance in intact animals. Residual cortical choline clearance correlated significantly with CHT‐immunoreactivity in lesioned and intact animals. Finally, synaptosomal choline uptake assays were conducted under conditions reflecting in vivo basal extracellular choline concentrations. Results from these assays confirmed the capacity of CHTs measured in vivo and indicated that diffusion of substrate away from the electrode did not confound the in vivo findings. Collectively, these results indicate that increases in extracellular choline concentrations, irrespective of source, are rapidly cleared by CHTs.
Models of the neuronal mediation of psychotic symptoms traditionally have focused on aberrations in the regulation of mesolimbic dopaminergic neurons, via their telencephalic afferent connections, ...and on the impact of abnormal mesolimbic activity for functions of the ventral striatum and its pallidal-thalamic-cortical efferent circuitry. Repeated psychostimulant exposure models major aspects of the sensitized activity of ventral striatal dopaminergic transmission that is observed in patients exhibiting psychotic symptoms. Based on neuroanatomical, neurochemical, and behavioral data, the hypothesis that an abnormally reactive cortical cholinergic input system represents a necessary correlate of a sensitized mesolimbic dopaminergic system is discussed. Moreover, the abnormal cognitive mechanisms that contribute to the development of psychotic symptoms are attributed specifically to the aberrations in cortical cholinergic transmission and to its consequences on the top-down regulation of sensory and sensory-associational input functions. Experimental evidence from studies demonstrating repeated amphetamine-induced sensitization of cortical cholinergic transmission and the ability of antipsychotic drugs to normalize the activity of cortical cholinergic inputs, and from experiments indicating the attentional consequences of manipulations that increase the excitability of cortical cholinergic inputs, supports this hypothesis. Relevant human neuropathological and psychopharmacological data are discussed, and the implications of an abnormally regulated cortical cholinergic input system for pharmacological treatment strategies are addressed. Given the role of cortical cholinergic inputs in gating cortical information processing, even subtle changes in the regulation of this cortexwide input system that represent a necessary transsynaptic consequence of sensitized mesolimbic dopaminergic transmission profoundly contribute to the neuronal mediation of psychotic symptoms.
Attentional processing is a crucial early stage in cognition and is subject to “top-down” regulation by prefrontal cortex (PFC). Top-down regulation involves modification of input processing in ...cortical and subcortical areas, including the posterior parietal cortex (PPC). Cortical cholinergic inputs, originating from the basal forebrain cholinergic system, have been demonstrated to mediate important aspects of attentional processing. The present study investigated the ability of cholinergic and glutamatergic transmission within PFC to regulate acetylcholine (ACh) release in PPC. The first set of experiments demonstrated increases in ACh efflux in PPC following AMPA administration into the PFC. These increases were antagonized by co-administration of the AMPA receptor antagonist DNQX into the PFC. The second set of experiments demonstrated that administration of carbachol, but not nicotine, into the PFC also increased ACh efflux in PPC. The effects of carbachol were attenuated by co-administration (into PFC) of a muscarinic antagonist (atropine) and partially attenuated by the nicotine antagonist mecamylamine and DNQX. Perfusion of carbachol, nicotine, or AMPA into the PPC did not affect PFC ACh efflux, suggesting that these cortical interactions are not bi-directional. These studies demonstrate the capacity of the PFC to regulate ACh release in the PPC via glutamatergic and cholinergic prefrontal mechanisms. Prefrontal regulation of ACh release elsewhere in the cortex is hypothesized to contribute to the cognitive optimization of input processing.
The posterior parietal cortex (PPC) plays an integral role in visuospatial attention. Evidence suggests that neuronal activity in the PPC predicts the allocation of attention to stimuli. The present ...experiment tested the hypothesis that in rats performing a sustained attention task, the detection of signals, as opposed to missed signals, is associated with increased PPC unit activity. Single unit activity was recorded from the PPC of rats and analyzed individually and as a population vector for each recording session. A population of single units (28/111) showed significant activation evoked by signals on trials resulting in correct performance (hits). A smaller population of neurons (three/111) was activated on trials in which signals were not detected by the animals (misses). Analysis of populations of simultaneously recorded neurons indicated increased activation predicting signal detection; no population of neurons was activated on trials in which the animal incorrectly pressed the hit lever following nonsignals. The increased, hit-predicting activity was not modulated by signal duration or the presence of a visual distractor, although the distractor reduced the number of trials in which hit-predicting activity and subsequent correct detection occurred. These findings indicate that attentional signal processing in the PPC integrates successful detection of signals.
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