quantification-information-encoded-gene-expression-levels-during

Quantification of Information Encoded by Gene Expression Levels During Lifespan Modulation Under Broad-range Dietary Restriction in <em>C. elegans</em>

Sensory systems allow animals to detect, process, and respond to their environment. Food abundance is an environmental cue that has profound effects on ...

King's College London

Spontaneously hypertensive rats (SHR) represent an animal model of cognitive decline associated with hypertension. Few studies have systematically investigated this decline in aging. We assessed spatial learning performances of SHR, the genetically similar Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD), in a water maze (WM) task. The following age ranges were studied: 6, 12, and 20 months. The results demonstrated that all three strains show the same level of impairment at the age of 20 months. The rate of cognitive decline, however, is different: both SHR and WKY show moderate degrees of impairment at all age ranges, while SD display good cognitive abilities at 6 months, declining at 12, and reaching the performance level of the other two groups at 20 months. Besides, the nine groups showed substantial differences in swim velocity and WKY exhibited a peculiar motor behavior. These results suggest the following: (a) the decline in cognitive level exhibits different trends in the three strains; (b) learning impairment of aged SHR might not be entirely explained by hypertension; (c) WKY should be used cautiously as normotensive control for SHR, due to their unusual behavior and low learning abilities; (d) analysis of escape distances is mandatory for the comparison of different strains in the WM test.

Does hypertension alone lead to cognitive decline in spontaneously hypertensive rats?

Cannabinoids, the active components of marijuana, are presumed to affect memory by an action on long-term potentiation. However, these molecules also reduce hippocampal glutamatergic neurotransmission. To distinguish the two activities, we studied the effects of the synthetic cannabinoid (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphtalenylmethanone (Win 55,212-2, 10 microM) on CA1 hippocampal responses generated by the activation of two independent pathways, one of which was potentiated with a tetanic stimulation. The results of the study show the following: (a) the drug does not affect long-term potentiation provided that the responses are compared to those obtained in the unpotentiated control pathway; (b) Win 55,212-2 increases post-tetanic potentiation.

Effects of Win 55,212-2 on hippocampal CA1 long-term potentiation in experiments controlled for basal glutamatergic synaptic transmission.

Cannabinoids, the active components of marijuana, affect memory and hippocampal neurotransmission. It has been claimed that nabilone, a synthetic cannabinoid endowed with antiemetic properties, has a peculiar profile of actions. We studied the effects of the drug on spatial learning and in vitro hippocampal CA1 electrophysiology in the rat. Nabilone (0.1, 0.5, and 1.0 mg/kg ip) does not impair place learning in a water maze task, whereas Delta(8)-tetrahydrocannabinol (Delta(8)-THC) disrupts this function. At concentrations ranging from 1 nM to 10 microM nabilone does not influence basal glutamatergic neurotransmission, which is decreased by Delta(8)-THC. Although cannabinoids have been consistently reported to affect synaptic plasticity, nabilone 1 microM does not change paired-pulse facilitation, long-term potentiation and the magnitude of long-term depression. However, the time course of the latter phenomenon is significantly changed by the drug, the depression being lower than in control experiments from 7 to 35 min postinduction. Altogether, our data indicate that there might be differences in the effects of agonists for central cannabinoid receptors, which could help to understand the pharmacology of this class of molecules. The results also suggest that amnesia induced by cannabinoids be possibly related to their effects on hippocampal neurotransmission. The study supports the use of nabilone in conditions the course of which is complicated by cognitive impairment.

Effects of the synthetic cannabinoid nabilone on spatial learning and hippocampal neurotransmission.

During the last few years there has been a growing awareness of behavioral and psychological symptoms of dementia (BPSD). These symptoms are usually classified in syndromes, which include psychosis, depression, agitation and sleep disturbances. BPSD have a major impact on the clinical course, prognosis and the quality of life of patients and caregivers. Moreover, BPSD considerably increase the social costs of dementia, since they often result in institutionalization. The therapy of BPSD was initially based on an empirical syndromic approach. However, in more recent years the efficacy and safety of treatments for these conditions have been tested in several controlled clinical trials. This paper addresses some of the methodological and regulatory issues that are relevant to the conducting of clinical trials for BPSD.

[Methodological and regulatory features of clinical trials for behavioral and psychological symptoms in the course of dementia].

The effects of three species of Hypericum (H.) on mice motor activity were compared in an automated open field test. Methanol extracts of H. perforatum L., H. hircinum L. and H. perfoliatum L. were tested at doses ranging from 2.5 to 200 mg i.p. H. hircinum decreased locomotion at most dose levels. Moreover, a dose of 200 mg/kg of all three herbal species sharply decreased motor activity. Ten mg/kg of H. perforatum, a dose that is comparable to that endowed with antidepressant effects in humans, tended to increase exploration and stereotypic activity and to decrease immobility. The study suggests that there are differences in the neuropharmacological actions of the three plant extracts. However, common constituents might explain the reduced motor activity observed at high dose levels.

Differential effects of three species of Hypericum in an open field test.

The mechanism whereby the morphology and connectivity of the dendritic tree is regulated depends on an actin dynamics that, in turn, is controlled by Rho GTPases, a family of small GTP-binding proteins encompassing Rho, Rac, and Cdc42 subfamilies. Cytotoxic necrotizing factor 1 (CNF1), a protein toxin from Escherichia coli, constitutively activates Rho GTPases, thus leading to remodeling of the actin cytoskeleton in intact cells. Here, we show that the modulation of cerebral RhoA and Rac1 activity induced by CNF1 in mice leads to (i) rearrangement of cerebral actin cytoskeleton, (ii) enhanced neurotransmission and synaptic plasticity, and (iii) improved learning and memory in various behavioral tasks. The effects persist for weeks and are not observed in mice treated with a recombinant CNF1, in which the enzymatic activity was abolished by substituting serine to cysteine at position 866. The results suggest that learning ability can be improved through pharmacological manipulation of neural connectivity.

Enhancement of learning and memory after activation of cerebral Rho GTPases.

Cerebral Rho GTPases are crucially involved in cognitive abilities. This activity is thought to be related to the regulation of actin polymerization and, thereby, of the shape of the dendritic tree. Here we report that Cytotoxic Necrotizing Factor 1 (CNF1, 1fmol/kgicv), a bacterial protein endowed with Rho GTPase activating properties, enhances working memory for object location/discrimination in C57BL/6 mice. CNF1 selectively increased the exploration of a specific familiar object moved to a position that had been previously occupied by another familiar object. Conversely, the treatment left unaffected (i) exploration of a familiar object moved to a location that was previously unoccupied and (ii) exploration of a novel object. The effects were associated with changes in Rho GTPase status, since CNF1 C866S, a recombinant CNF1 in which the enzymatic activity was abolished through substitution of serine to cysteine at position 866, was ineffective in all the experiments. The study suggests that working memory for specific object-location associations critically depends on neural connectivity. It also confirms the therapeutic potential of the manipulation of Rho GTPase signaling in the modulation of memory processes.

The Rho GTPase activating CNF1 improves associative working memory for object-in-place.

Gorlin-Goltz (GG) syndrome is an inherited autosomal dominant condition. Its diagnosis may be clinically confirmed by checking either major or minor signs that define the diagnostic criteria. It may occur that, although GG syndrome is a well-known condition, only the specific symptom could be observed by different specialists. Therefore, the patient cannot be placed into an always complex clinical panel. We introduce an example in this report. Throughout a 20-year clinical history characterized by the lack of proper diagnosis and missed follow-up operations, a patient with GG syndrome underwent partial amputation of the jaw after severe complications. A 52-year-old man required an implant-prosthetic rehabilitation since becoming edentulous after a partial resection of the jaw due to a keratocyst, which was later reconstructed through a free fibula flap. The observation of a typical phenotype and various symptoms that succeeded for longer than 20 years, with anamnestic evaluation and clinical examination, led us to suspect a complex pathologic condition such as GG syndrome, which was not previously considered, although the patient had undergone several polyspecialistic evaluations. Diagnosis has been eventually confirmed by a genetic study, which was always mandatory. The simultaneous presence of muscular and skeletal malformations, basocellular nevi, and multiple cysts of the jaw can represent signs linking to a condition such as GG syndrome. There are many syndromes involving the head and neck region, and specialists are supposed to be alerted when faced with similar typical expressions associated with a characteristic soma so as to avoid delays in diagnosing the syndrome.

Follicular cyst of the jaw developing into a keratocyst in a patient with unrecognized Gorlin-Goltz syndrome.

Progressive hemifacial atrophy or Parry-Romberg syndrome is an uncommon degenerative and poorly understood condition characterized by progressive atrophy of 1 side of the face. It may involve several layers of tissue manifesting itself in a more or less aggressive form (mild, moderate, and severe). Generally, the restoration of contour and symmetry are the goals of the therapy in patients affected by this syndrome. In this article, we present the technique and the 6-year postsurgery result of a case of Parry-Romberg syndrome treated with 1-stage anterior lifting, removal of superficial muscular aponeurotic system, and autologous fat transplantation because the patient requested to recover more than atrophy and also 20 years of lost youth.

Rhytidectomy associated with autologous fat transplantation in Parry-Romberg syndrome.

Rho GTPases are key regulators of the activity-dependent changes of neural circuits. Besides being involved in nervous system development and repair, this neural structural plasticity is believed to constitute the cellular basis of learning and memory. Here we report that concurrent modulation of cerebral Rho GTPases, including Rac, Rho and Cdc42 subfamilies, by Cytotoxic Necrotizing Factor 1 (CNF1, 10 fmol/kg intracerebroventricularly) improves object recognition in both C57BL/6J and CD1 mice. The improvement is long lasting, as it is still observed 90 days post treatment. At this time, the treatment is associated with enhancement of neurotransmission and long-term potentiation. The effects depend on changes in Rho GTPase status, since the recombinant molecule CNF1 C866S, in which the enzymatic activity was abolished through substitution of serine to cysteine at position 866, is ineffective. The study confirms the role of Rho GTPases in learning and suggests that a single administration of CNF1 is effective for a long time after administration. In general, the long-lasting cognition enhancing effect of CNF1 might be beneficial for the treatment of CNS disorders. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Long-lasting efficacy of the cognitive enhancer cytotoxic necrotizing factor 1.

Small GTPases of the Rho family, including Rho, Rac and CDC42 subfamilies, play key role in neural connectivity and cognition. The pharmacological modulation of these regulatory proteins is associated with enhancement of learning and memory. We sought to determine whether the modulation of cerebral Rho GTPases may correct behavioral disturbances in a mouse model of Alzheimer's disease (AD). TgCRND8 mice show early-onset Abeta amyloid deposits associated with deficits in several cognitive tasks. We report that four-month old TgCRND8 mice display (a) increased locomotor activity in an open field, (b) mild deficits in the learning of a fixed platform position in a water maze task. More markedly, after displacement of the escape platform, TgCRND8 mice exhibit impairment in the learning of the novel position (reversal learning), as they perseverate searching in the familiar position. The administration of the Rho GTPase activator Cytotoxic Necrotizing Factor 1 (CNF1, 1.0 fmol kg(-1) intracerebroventricularly) reduces locomotor hyperactivity and corrects the deficits in reversal learning, thus re-establishing normal behavioral plasticity. We conclude that the pharmacological modulation of Rho GTPase signaling might be beneficial for the treatment of AD. Reversal learning in TgCRND8 mice may represent a convenient pre-clinical assay for the efficacy of therapeutic interventions in AD.

Behavioral effects of Rho GTPase modulation in a model of Alzheimer's disease.

We address the issue of minimizing the heat generated when erasing the information stored in an array of quantum dots in finite time. We identify the fundamental limitations and trade-offs involved in this process and analyze how a feedback operation can help improve it.

Finite-time erasing of information stored in fermionic bits.

Brain activity is associated with structural changes in the neural connections. However, in vivo imaging of the outer cortical layers has shown that dendritic spines, on which most excitatory synapses insist, are predominantly stable in adulthood. Changes in dendritic spines are governed by small GTPases of the Rho family through modulation of the actin cytoskeleton. Yet, while there are abundant data about this functional effect of Rho GTPases in vitro, there is limited evidence that Rho GTPase signaling in the brain is associated with changes in neuronal morphology. In the present work, both chronic in vivo two-photon imaging and Golgi staining reveal that the activation of Rho GTPases in the adult mouse brain is associated with little change of dendritic spines in the apical dendrites of primary visual cortex pyramidal neurons. On the contrary, considerable increase in spine density is observed (i) in the basal dendrites of the same neurons (ii) in both basal and apical dendrites of the hippocampal CA1 pyramidal cells. While confirming that Rho GTPase-dependent increase in spine density can be substantial, the study indicates region and dendrite selectivity with relative stability of superficial cortical circuits.

Rho GTPase-dependent plasticity of dendritic spines in the adult brain.

Alzheimer's disease (AD) is characterized by a wide loss of synapses and dendritic spines. Despite extensive efforts, the molecular mechanisms driving this detrimental alteration have not yet been determined. Among the factors potentially mediating this loss of neuronal connectivity, the contribution of Rho GTPases is of particular interest. This family of proteins is classically considered a key regulator of actin cytoskeleton remodeling and dendritic spine maintenance, but new insights into the complex dynamics of its regulation have recently determined how its signaling cascade is still largely unknown, both in physiological and pathological conditions. Here, we review the growing evidence supporting the potential involvement of Rho GTPases in spine loss, which is a unanimously recognized hallmark of early AD pathogenesis. We also discuss some new insights into Rho GTPase signaling framework that might explain several controversial results that have been published. The study of the connection between AD and Rho GTPases represents a quite unchartered avenue that holds therapeutic potential.

The potential role of rho GTPases in Alzheimer's disease pathogenesis.

Recent evidence suggests an early involvement of dopaminergic (DA) processes and terminals in Parkinson's disease (PD). The arborization of neurons depends on the actin cytoskeleton, which in turn is regulated by small GTPases of the Rho family, encompassing Rho, Rac and Cdc42 subfamilies. Indeed, some reports point to a role for Rac and Cdc42 signaling in the pathophysiology of inherited parkinsonisms. We thus investigated the potential therapeutic effect of the modulation of cerebral Rho GTPases in PD. Cytotoxic necrotizing factor 1 (CNF1), a 114 kDa protein toxin produced by Escherichia coli, permanently activates RhoA, Rac1 and Cdc42 in intact cells. We report that the modulation of Rho GTPases by CNF1 results in hypertrophy of DA cell processes of cultured substantia nigra neurons, including increase in length, branching and varicosity. In vivo, the treatment corrects long-standing motor and biochemical asymmetries and restores degenerated nigrostriatal DA tissue after 6-hydroxydopamine lesion. We conclude that the pharmacological modulation of Rho GTPases shows neurorestorative potential and represents a promising avenue in the treatment PD. The study also suggests that naturally occurring molecules acting on Rho GTPase signaling, such as some bacterial protein toxins, might play a role in the development of PD.

Therapeutic effects of the Rho GTPase modulator CNF1 in a model of Parkinson's disease.

Neuroendocrine circuits encode environmental information via changes in gene expression and other biochemical activities to regulate physiological responses. Previously, we showed that daf-7 TGFβ and tph-1 tryptophan hydroxylase expression in specific neurons encode food abundance to modulate lifespan in Caenorhabditis elegans, and uncovered cross- and self-regulation among these genes (Entchev et al., 2015). Here, we now extend these findings by showing that these interactions between daf-7 and tph-1 regulate redundancy and synergy among neurons in food encoding through coordinated control of circuit-level signal and noise properties. Our analysis further shows that daf-7 and tph-1 contribute to most of the food-responsiveness in the modulation of lifespan. We applied a computational model to capture the general coding features of this system. This model agrees with our previous genetic analysis and highlights the consequences of redundancy and synergy during information transmission, suggesting a rationale for the regulation of these information processing features.

Article	Year
Does hypertension alone lead to cognitive decline in spontaneously hypertensive rats? Behavioural brain research\| PubMed ID: 12191797	2002
Effects of Win 55,212-2 on hippocampal CA1 long-term potentiation in experiments controlled for basal glutamatergic synaptic transmission. European journal of pharmacology\| PubMed ID: 12398912	2002
Effects of the synthetic cannabinoid nabilone on spatial learning and hippocampal neurotransmission. Pharmacology, biochemistry, and behavior\| PubMed ID: 12895676	2003
[Methodological and regulatory features of clinical trials for behavioral and psychological symptoms in the course of dementia]. Annali dell'Istituto superiore di sanita\| PubMed ID: 14587227	2003
Differential effects of three species of Hypericum in an open field test. Phytotherapy research : PTR\| PubMed ID: 17160972	2007
Enhancement of learning and memory after activation of cerebral Rho GTPases. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 17202256	2007
The Rho GTPase activating CNF1 improves associative working memory for object-in-place. Behavioural brain research\| PubMed ID: 20362628	2010
Follicular cyst of the jaw developing into a keratocyst in a patient with unrecognized Gorlin-Goltz syndrome. The Journal of craniofacial surgery\| PubMed ID: 20485063	2010
Rhytidectomy associated with autologous fat transplantation in Parry-Romberg syndrome. The Journal of craniofacial surgery\| PubMed ID: 21558893	2011
Long-lasting efficacy of the cognitive enhancer cytotoxic necrotizing factor 1. Neuropharmacology\| PubMed ID: 22659407	2013
Behavioral effects of Rho GTPase modulation in a model of Alzheimer's disease. Behavioural brain research\| PubMed ID: 23026376	2013
Finite-time erasing of information stored in fermionic bits. Physical review. E, Statistical, nonlinear, and soft matter physics\| PubMed ID: 23410287	2013
Rho GTPase-dependent plasticity of dendritic spines in the adult brain. Frontiers in cellular neuroscience\| PubMed ID: 23734098	2013
The potential role of rho GTPases in Alzheimer's disease pathogenesis. Molecular neurobiology\| PubMed ID: 24452387	2014
Therapeutic effects of the Rho GTPase modulator CNF1 in a model of Parkinson's disease. Neuropharmacology\| PubMed ID: 27350290	2016
Genetic control of encoding strategy in a food-sensing neural circuit. eLife\| PubMed ID: 28166866	2017
A neurorestorative approach to Parkinson's disease. Oncotarget\| PubMed ID: 28423348	2017

Giovanni Diana

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