Translational animal models of autism and neurodevelopmental disorders.

Autism is a neurodevelopmental disorder whose diagnosis is based on three behavioral criteria: unusual reciprocal social interactions, deficits in communication, and stereotyped repetitive behaviors with restricted interests. A large number of de novo single gene mutations and chromosomal deletions are associated with autism spectrum disorders. Based on the strong genetic evidence, mice with targeted mutations in homologous genes have been generated as translational research tools. Mouse models of autism have revealed behavioral and biological outcomes of mutations in risk genes. The field is now poised to employ the most robust phenotypes in the most replicable mouse models for preclinical screening of novel therapeutics

The consequence of fetal ethanol exposure and adolescent odor re-exposure on the response to ethanol odor in adolescent and adult rats

<p>Abstract</p> <p>Background</p> <p>An epidemiologic predictive relationship exists between fetal ethanol exposure and the likelihood for adolescent use. Further, an inverse relationship exists between the age of first experience and the probability of adult abuse. Whether and how the combined effects of prenatal and adolescent ethanol experiences contribute to this progressive pattern remains unknown. Fetal ethanol exposure directly changes the odor attributes of ethanol important for both ethanol odor preference behavior and ethanol flavor perception. These effects persist only to adolescence. Here we tested whether adolescent ethanol odor re-exposure: (Experiment 1) augments the fetal effect on the adolescent behavioral response to ethanol odor; and/or (Experiment 2) perpetuates previously observed adolescent behavioral and neurophysiological responses into adulthood.</p> <p>Methods</p> <p>Pregnant rats received either an ethanol or control liquid diet. Progeny (observers) experienced ethanol odor in adolescence via social interaction with a peer (demonstrators) that received an intragastric infusion of either 1.5 g/kg ethanol or water. Social interactions were scored for the frequency that observers followed their demonstrator. Whole-body plethysmography evaluated the unconditioned behavioral response of observers to ethanol odor in adolescence (P37) or adulthood (P90). The olfactory epithelium of adults was also examined for its neural response to five odorants, including ethanol.</p> <p>Results</p> <p>Experiment 1: Relative to fetal or adolescent exposure alone, adolescent re-exposure enhanced the behavioral response to ethanol odor in P37 animals. Compared to animals with no ethanol experience, rats receiving a single experience (fetal or adolescent) show an enhanced, yet equivalent, ethanol odor response. Fetal ethanol experience also increased olfactory-guided following of an intoxicated peer. Experiment 2: Combined exposure yielded persistence of the behavioral effects only in adult females. We found no evidence for persistence of neurophysiological effects in either sex.</p> <p>Conclusion</p> <p>Fetal ethanol exposure influences adolescent re-exposure, in part, by promoting interactions with intoxicated peers. Re-exposure subsequently enhances ethanol odor responsivity during a key developmental transition point for emergent abuse patterns. While persistence of behavioral effects occurred in females, the level of re-exposure necessary to uniformly yield persistence in both sexes remains unknown. Nonetheless, these results highlight an important relationship between fetal and adolescent experiences that appears essential to the progressive pattern of developing ethanol abuse.</p

Reproductive isolation in smooth and palmate newts (Triturus vulgaris vulgaris and T. helveticus helveticus)

This thesis reports a study of reproductive isolation between two closely related sympatric British species of amphibian, the Smooth newt, Triturus vulgaris vulgaris and the Palmate newt, T, helveticus helveticus. Investigation shows that reproductive isolation is not attributable to differences in habitat, the timing of courtship or the failure of spermatophores to adhere to the cloaca of a heterospecific female and it is demonstrated that a proportion of FI hybrid larvae are capable of survival beyond metamorphosis; by elimination, the lack of naturally occurring hybrids is primarily a consequence of sexual isolation. Techniques for distinguishing both purebred and hybrid larvae and adult newts of both sexes and species based on differences in their external morphology are evaluated. The most suitable distinguishing characters (on which visual discrimination in newts may be based) are described. The variation in the courtship behaviour of T. h. helveticus is described in detail and compared to that of T. v, vulgaris. The similarity in form and transition of male acts suggests that qualitative differences in display and order of acts are not the primary source of information on which female discrimination is based. Quantitative differences in the proportion of acts performed probably serve to emphasise species-specific cues which play a direct role in sexual isolation. À causal analysis is carried out on a relatively recently recognised I. h. helveticus display act, the wiggle. Evidence is presented that the function of this act is to re- attract a female that is becoming unreceptive and it does not appear to contribute to reproductive isolation. Interspecific mating trials show that female J. h. helveticus are less receptive to heterospecific courtship than conspecific courtship. Male T. V. vulgaris display less vigorously to heterospecific females manipulated by means of a harness to perform positive behaviour than to conspecific females. It is demonstrated that male T. h. helveticus show selectivity towards conspecific females over heterospecific females on the basis of both visual and olfactory cues alone, whereas in male T. v. vulgaris and female T. v, vulgaris, the same preference is only observed on the basis of olfaction. When presented with an artificial fanning tail mimic, females of both species preferred the faster (T. h. helveticus) fan speed. It is suggested that sexual isolation is the consequence of a dual system in which males fail to recognise, or are less receptive to the olfactory and/or visual cues produced by heterospecific females and consequently do not initiate courtship with them. Where interspecific courtship does occur, the stimulation produced by the male is inadequate to raise the receptivity of the female at a high enough rate for the encounter to progress to spermatophore transfer

Some consequences for social behavior of perinatal asphyxia and c-section delivery of full term male rats

The process of birth (parturition) has a critical impact on normal human development. Any deviations from the typical parturition process are defined clinically as birth complications, and have been linked to the development of neurological deficits. Two relatively common types of consequences from birth complications are perinatal asphyxia and Caesarean Section delivery (C-section); however, C-section is becoming more common as a matter of choice (elective C-section delivery) rather than as a consequence of some birth complication (Barber et al., 2011; Martin et al., 2012). The two consequences of birth complications differ: perinatal asphyxia involves extended periods of oxygen deprivation during delivery, whereas elective C-section deprives the fetus of the typical conditions associated with a vaginal delivery. Animal research reveals that both perinatal asphyxia and C-section lead to increased expression of dopamine in the mesolimbic dopaminergic pathway. Since this dopaminergic pathway is important for learning, attention, working memory, motivation, movement and mood there is evidence that such increases in dopamine expression result in deficits in these functions. Because the mesolimbic dopaminergic system innervates the hypothalamus, previous research suggested that the complication of perinatal asphyxia results in an increased sensitivity to stress via alterations in the functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Such alterations may be apparent in the development of sensitivity to stressful situations. One test of sensitivity to stressful situations for rodents is to present a resident adult male with an adult male intruder. This social situation can be marked by investigatory and aggressive behaviors on the part of the resident male. The hypothesis for this thesis is that perinatal asphyxia and C-section delivery of male rats will result in differences in adult investigatory and aggressive social behaviors in this stress test. This study compares the social behavior of 55 day old, postpubertal male rats exposed to asphyxia and C-section at birth, with that of vaginally delivered rats. The social behaviors also were examined in relation to neuroanatomical and neurochemical alterations in dopamine transmission, specifically in the nucleus accumbens

Attention Enhances the Retrieval and Stability of Visuospatial and Olfactory Representations in the Dorsal Hippocampus

Attention enhances the encoding and retrieval of olfactory and visuospatial representations by modulating place field stability, firing rate, and neuronal synchronization of pyramidal cells in the hippocampus

An impairment in sniffing contributes to the olfactory impairment in Parkinson's disease

Although the presence of an olfactory impairment in Parkinson's disease (PD) has been recognized for 25 years, its cause remains unclear. Here we suggest a contributing factor to this impairment, namely, that PD impairs active sniffing of odorants. We tested 10 men and 10 women with clinically typical PD, and 20 age- and gender-matched healthy controls, in four olfactory tasks: (i) the University of Pennsylvania smell identification test; (ii and iii) detection threshold tests for the odorants vanillin and propionic acid; and (iv) a two-alternative forced-choice detection paradigm during which sniff parameters (airflow peak rate, mean rate, volume, and duration) were recorded with a pneomatotachograph-coupled spirometer. An additional experiment tested the effect of intentionally increasing sniff vigor on olfactory performance in 20 additional patients. PD patients were significantly impaired in olfactory identification (P < 0.0001) and detection (P < 0.007). As predicted, PD patients were also significantly impaired at sniffing, demonstrating significantly reduced sniff airflow rate (P < 0.01) and volume (P < 0.002). Furthermore, a patient's ability to sniff predicted his or her performance on olfactory tasks, i.e., the more poorly patients sniffed, the worse their performance on olfaction tests (P < 0.009). Finally, increasing sniff vigor improved olfactory performance in those patients whose baseline performance had been poorest (P < 0.05). These findings implicate a sniffing impairment as a component of the olfactory impairment in PD and further depict sniffing as an important component of human olfaction

Sexual Motivation and Mate Choice in the Female Smooth Newt, <i>Triturus vulgaris</i>

This thesis describes a study of sexual motivation and mate choice in the female smooth newt, Triturus vulgaris. Chapter one introduces the species' natural and life histories and sexual behaviour. It also describes the different approaches (causal and functional) that have been employed and explains why a female perspective has been particularly emphasised. Chapter three reports the results of the preliminary study of female sexual motivation which provided the basis for further investigation. Chapter four discusses some of the results of the follow-up study. Female sexual responsiveness was monitored over a complete breeding season. The relationship between inseminations and egg-laying was investigated. This chapter essentially looked at female sexual responsiveness from a functional perspective. It was found to vary greatly, and was affected by egg-laying and time of season. Chapter five discusses female sexual responsiveness in the same study reported in Chapter four, but from a causal perspective. Female sexual behaviour was described in detail, behaviour patterns were defined and motivation scores were devised to examine variation over the season. Chapter six examines female mate choice. Aspects of male morphology, spermatophore pick-up and partner familiarity were investigated. Females were found to show discrimination for larger-crested males, but this discrimination varied and was related to sexual motivation. Chapter seven reports an investigation into how females perceive the stimuli presented to them by the male during his display. The relative importance of visual and olfactory stimuli was studied, as well as the effect of the combination of both sets of cues. Chapter eight re-examines the value to this area of research of using the different approaches and perspectives employed here and discusses the results of all the experiments performed

Children’s early reading through the sense of smell: a typology of olfactory engagement

We investigated adult–child shared book reading of olfactory books that stimulate the sense of smell through scratch-and-sniff surfaces. We observed ten adult–child dyads reading olfactory books at home and documented the characteristics and quality markers of their olfactory engagement. Drawing on the principles of learning sciences and socio-cultural learning theories, we propose a Typology of Olfactory Engagement that brings to the fore the potential of actively engaging the sense of smell during shared book reading. We outline how the Typology of Olfactory Engagement can serve as a basis for future studies exploring adult–child interaction in home learning environments.publishedVersio

Olfaction-enhanced multimedia: Perspectives and challenges

This is the post-print version of the Article. The official published version can be accessed from the link below - Copyright @ 2011 Springer VerlagOlfaction—or smell—is one of the last challenges which multimedia and multimodal applications have to conquer. Enhancing such applications with olfactory stimuli has the potential to create a more complex—and richer—user multimedia experience, by heightening the sense of reality and diversifying user interaction modalities. Nonetheless, olfaction-enhanced multimedia still remains a challenging research area. More recently, however, there have been initial signs of olfactory-enhanced applications in multimedia, with olfaction being used towards a variety of goals, including notification alerts, enhancing the sense of reality in immersive applications, and branding, to name but a few. However, as the goal of a multimedia application is to inform and/or entertain users, achieving quality olfaction-enhanced multimedia applications from the users’ perspective is vital to the success and continuity of these applications. Accordingly, in this paper we have focused on investigating the user perceived experience of olfaction-enhanced multimedia applications, with the aim of discovering the quality evaluation factors that are important from a user’s perspective of these applications, and consequently ensure the continued advancement and success of olfaction-enhanced multimedia applications

Characterization of the Kidins220 CaMKIICre conditional KO mouse line

Kidins220 (Kinase-D interacting substrate of 220 kDa) is a scaffold transmembrane protein abundantly expressed in the nervous system. Mutations in the KIDINS220 gene have been correlated with psychiatric disorders and with the recently described SINO syndrome, characterized by spastic paraplegia, intellectual disability, syntagmus and obesity. Kidins220 is involved in several neuronal functions regulated by neurotrophic factors, including neuronal survival, differentiation and synaptic plasticity. Previous work with the complete KO mouse model for Kidins220 evidenced the crucial role of this protein in neuronal and cardiovascular development since its embryonic ablation is lethal. Thus to gain a comprehensive understanding of the role of Kidins220 in the adult mouse, a Cre/loxP based conditional KO (cKO) mouse model was generated, in which the Ca2+/ Calmodulin-dependent kinase-II (CaMKII) promoter drives Cre expression, and consequently protein deletion specifically in the postnatal forebrain. The characterization of the Kidins220 cKO model has been accomplished through diverse approaches: behavioural experiments, brain and neuron morphological analysis, molecular signalling from brain slices and cultures, protein and gene expression assessment. cKO mice display alterations in anxiety levels and social behaviour, with a clear impairment in social memory. At the morphological level, data show reduced dendritic branching in cortical and hippocampal neurons, while at the molecular level, neuronal response to brain-derived neurotrophic factor (BDNF) stimulation is blunted, as well as the mitogen-activated protein kinase (MAPK) pathway activation. The behavioural profile of these animals provides useful knowledge about the pathophysiology of Kidins220, indicating that alterations of this protein expression may have important consequences on human pathologies of the cognitive and social sphere. Some psychiatric diseases are highly inheritable, and their causes have been traced back to genetic alterations such as point mutations and epigenetic modifications. A better understanding of such inheritable traits will provide us with a better knowledge of the cellular and physiological alterations underlying the behavioural and cognitive symptomatology of patients. In this respect, the knowledge of Kidins220 function will contribute to further elucidate the neuropathological mechanisms underlying some psychiatric diseases