This thesis examined whether it is possible to enhance core elements of the information processing system with specific forms of environmental stimulation. The first series of experiments demonstrated that a preweaning environmental enrichment procedure that provided 60 minutes of daily multisensory stimulation accelerated the development of long-term contextual memory and enhanced inhibitory processing in young rats. That is, whilst stimulated and non-stimulated rats exhibited long-term memory of a context at 26 days of age, only stimulated rats showed this ability at 18 days of age. In addition, stimulated rats showed a faster rate of extinction of long-term contextual memory at 21 days of age, which was taken as evidence of enhanced inhibitory learning (i.e., context ??? no US) in these rats. Subsequent experiments with adult rats demonstrated that a combination of preweaning multisensory stimulation and postweaning rearing in an enriched environment improved the (1) specificity of long-term contextual memory, (2) speed of contextual information processing, and (3) availability of attentional resources. More specifically, enriched-reared rats demonstrated superior ability to discriminate between two similar contexts in comparison to standard-reared rats. In addition, enriched-reared rats showed superior memory of a context when there was limited time available to form a memory of that context. This finding was taken to indicate that rats that receive environmental enrichment are able to process contextual information more rapidly. Finally, standard-, but not enriched-, reared rats showed less conditioning to a discrete stimulus when it was presented in combination with a stronger stimulus during training compared to when it was presented by itself. The finding that enriched-reared rats did not show this overshadowing effect suggests that these rats have greater availability of attentional resources to divide between two stimuli that are competing for attention. The experiments with rats were followed by two experiments with children that investigated the effects of a computerised cognitive training procedure on information-processing speed. These experiments demonstrated that 30-minutes per weekday of training in rapid decision-making for three to five weeks improved children???s performance on two tests of processing speed (i.e., a choice reaction time and odd-man-out task). In addition, the speeded training improved children???s ability to sustain their attention and inhibit impulsive responses on a continuous performance test (Test of Variables of Attention). The cognitive training procedure had no effect on children???s performance on a measure of fluid intelligence (Raven???s Standard Progressive Matrices). The results of the experiments reported in this thesis suggest that a number of fundamental cognitive processes can be modified by environmental conditions that place increasing demands on the information-processing system. A neurobiological model, focusing on myelin, axon diameter, and the glutamatergic, glucocorticoid, noradrenergic, and cholinergic systems, was proposed in order to explain the observed effects of environmental stimulation on cognition in children and rats. The rationale for attempting to enhance fundamental cognitive processes was that improving these processes should ultimately improve general intellectual functioning. With respect to this aim, the correlational data from the present experiments with children revealed promising trends towards greater improvements on the tests of fundamental cognitive processes in those children in the training group with slower processing speed at the start of the intervention. This finding suggests that cognitive training may be even more effective at enhancing processing speed and other fundamental cognitive processes in children with intellectual impairments???who reportedly have slower processing speed than normal children. However, the extent to which training-related improvements in fundamental cognitive processes generalise to improvements in general cognitive functioning is unclear. That is, there is insufficient evidence that processing speed and other fundamental cognitive processes are causally related to intelligence. It is therefore essential that future cognitive training research is mindful of related developments within the intelligence and information processing literature.

Domestication has resulted in animals with broad variations between as well as within breeds, which allows for the selection and breeding of animals for preferred traits. This selection has affected both the genotypes and phenotypes of animals. In dogs, it has allowed for breeding for different purposes, such as companionship or the performance of specific tasks, e.g., herding, hunting, searching and protecting. Each of these types of working dogs has specific traits that are, in part, controlled by genes; however, genes are not solely responsible for the variations in the traits of an individual. The environment also plays a role, which has been studied in rodents and primates in recent decades. For instance, it has been shown that the amount of maternal care that a rat receives as a pup affects its temperament later in life; the more maternal care, i.e., licking, grooming and arched-back nursing (LG-ABN), that a rat receives, the more stress resistant, less reactive and more explorative it will be as an adult. However, the question is whether this is also true for dogs, and the investigation of how temperament in dogs is affected by environmental factors early in life is the main objective of this thesis. Three of the studies presented in this thesis focused on investigating the general parameters, particularly maternal care, that influences offspring behaviour to contribute to the understanding of temperament development in military working dogs. One of these studies concentrated on the environmental factors that influence dogs early in life, and the results indicated that some factors, such as parity, litter size and birth season, affect temperament later in life. Another study investigated how females take care of their young, and the results demonstrated that females consistently vary in their maternal style during the first three weeks postpartum and that this variation affects the temperament of the offspring. The third study focused on factors in the home environment, and the results showed that dogs approved through the evaluative temperament test were significantly associated with being hyperactive or restless and having difficulty settling down in the home environment. However, those dogs were also left home alone for more hours in a day than non-approved dogs. To be able to operate functionally, a military working dog needs to possess certain traits, or a certain temperament, and a vital characteristic is the way it responds to and copes with stress. This was investigated during an evaluative temperament test used to select dogs suitable for further training. Surprisingly, the results showed that the dogs approved for further training had significantly higher levels of salivary cortisol both before and after the test compared with the non-approved dogs. These findings may be of profound importance for understanding individual variations in behaviour and improving breeding schemes for working dogs. / För över 15 000 år sedan började våra anfäder avla på vargar och lade då grunden för den uppsjö av olika hundraser vi ser idag. Exakt hur den här processen såg ut, när eller vart den startade vet vi faktiskt inte med säkerhet, men att vargen/hunden var det första djur att påbörja en sådan förändring, det vet vi. Att aktivt välja ut och avla på önskvärda egenskaper påverkar och förändrar gradvis djuret. Den här förändringen styrs i hög grad av gener, vilket medför att ett djurs s.k. genotyp förändras. Den här förändringsprocessen, där ett djur gradvis anpassas till ett liv som tamdjur, kallas för domesticering och innebär inte bara att djuret förändras genetiskt, utan också att den ändrar utseende och beteende, dvs. djurets fenotyp ändras också. Det är därför vi bl. a. ser så många olika hundraser som vi gör idag, allt från en liten hårlös Chihuahua till en stor raggig St. Bernard. Alla är de hundar, men de ser väldigt olika ut och har delvis olika egenskaper eller temperament. Det medför att de passar till att göra olika saker och därför också kan vara till stor nytta i samhället i allt från sällskapshunden som kan lära sig leta kantareller, till olika typer av tjänstehundar. Bra ledarhundar åt synskadade, polishundar som söker försvunna människor och narkotika, och försvarsmaktens tjänstehundar som kan förhindra angrepp eller terrorverksamhet genom att leta efter t ex. bomber och vapen - alla kan i förlängningen innebära ökad livskvalité och räddade människoliv. Men för det krävs att hunden passar för jobbet. Det är både generna, arvet och olika miljöfaktorer i den tidiga uppväxten som avgör egenskaperna hos en individ. Det är något som har visat sig gälla till exempel för råttor och primater. Studier på råttor har exempelvis pekat på att mängden omvårdnad en råtta får som liten (t ex hur mycket mamman slickar sina barn) påverkar dess egenskaper som vuxen. Och att ju mer omvårdnad de fått, desto mer stresståliga, mindre nervösa och mer nyfikna blev de. Även i studier på människor pekar resultaten i samma riktning. Men gäller detta även för våra hundar? För att öka kunskapen om och förståelsen för hur tidiga erfarenheter påverkar temperament, stress och arbetsförmåga hos våra blivande tjänstehundar i försvarsmakten har därför en rad olika studier på området genomförts. Den här avhandlingen fokuserar således på att undersöka vilka generella tidiga erfarenheter och faktorer i den tidiga uppväxtmiljön som tycks kunna vara med och påverka temperamentet hos våra tjänstehundar. Specifikt undersöker den hur tikens omvårdnad påverkar vissa egenskaper. Avhandlingen undersöker vidare hur stresståliga våra hundar är och hur detta yttrar sig i samband med de lämplighets test som hundarna genomgår i syfte att bedöma vilka individer som bör gå vidare till fortsatt träning efter ett och ett halvt års ålder. Resultaten i en studie visar att de hundar som bedömts som lämpliga vid lämplighetstestet något oväntat uppvisade ett högre påslag av stresshormonet kortisol, och i en annan studie att lämpliga hundar bedömts vara hyperaktiva/rastlösa och ha vissa svårigheter att ta det lugnt i hemmiljö. Detta samtidigt som de uppvisade en önskvärd temperamentsprofil vid uttagningsprovet, vilket kan antyda att dessa hundar är mer flexibla och motståndskraftiga mot stress, vilket skulle kunna vara resultatet av en lyckad avel. Vidare visade resultaten att det finns generella faktorer i den tidiga uppväxtmiljön, såsom tikens tidigare erfarenhet av att vara mamma, kullstorlek och när på året kullen föds, som är med och påverkar olika egenskaper. Den visar också att tikarnas sätt att ta hand om sina valpar varierade men var konsekvent under den första omvårdnadstiden på tre veckor och att det finns en koppling mellan mammans omvårdnads-stil och hur deras valpar blir som vuxna. Sammantaget visar avhandlingen att det finns faktorer i den tidiga uppväxtmiljön som påverkar temperamentet senare i livet på våra tjänstehundar. / <p>The ISBN <strong>987</strong>-91-7685-945-2 in the thesis is incorrect. Correct ISBN is <strong>978</strong>-91-7685-945-2.</p>

This thesis examined whether it is possible to enhance core elements of the information processing system with specific forms of environmental stimulation. The first series of experiments demonstrated that a preweaning environmental enrichment procedure that provided 60 minutes of daily multisensory stimulation accelerated the development of long-term contextual memory and enhanced inhibitory processing in young rats. That is, whilst stimulated and non-stimulated rats exhibited long-term memory of a context at 26 days of age, only stimulated rats showed this ability at 18 days of age. In addition, stimulated rats showed a faster rate of extinction of long-term contextual memory at 21 days of age, which was taken as evidence of enhanced inhibitory learning (i.e., context ??? no US) in these rats. Subsequent experiments with adult rats demonstrated that a combination of preweaning multisensory stimulation and postweaning rearing in an enriched environment improved the (1) specificity of long-term contextual memory, (2) speed of contextual information processing, and (3) availability of attentional resources. More specifically, enriched-reared rats demonstrated superior ability to discriminate between two similar contexts in comparison to standard-reared rats. In addition, enriched-reared rats showed superior memory of a context when there was limited time available to form a memory of that context. This finding was taken to indicate that rats that receive environmental enrichment are able to process contextual information more rapidly. Finally, standard-, but not enriched-, reared rats showed less conditioning to a discrete stimulus when it was presented in combination with a stronger stimulus during training compared to when it was presented by itself. The finding that enriched-reared rats did not show this overshadowing effect suggests that these rats have greater availability of attentional resources to divide between two stimuli that are competing for attention. The experiments with rats were followed by two experiments with children that investigated the effects of a computerised cognitive training procedure on information-processing speed. These experiments demonstrated that 30-minutes per weekday of training in rapid decision-making for three to five weeks improved children???s performance on two tests of processing speed (i.e., a choice reaction time and odd-man-out task). In addition, the speeded training improved children???s ability to sustain their attention and inhibit impulsive responses on a continuous performance test (Test of Variables of Attention). The cognitive training procedure had no effect on children???s performance on a measure of fluid intelligence (Raven???s Standard Progressive Matrices). The results of the experiments reported in this thesis suggest that a number of fundamental cognitive processes can be modified by environmental conditions that place increasing demands on the information-processing system. A neurobiological model, focusing on myelin, axon diameter, and the glutamatergic, glucocorticoid, noradrenergic, and cholinergic systems, was proposed in order to explain the observed effects of environmental stimulation on cognition in children and rats. The rationale for attempting to enhance fundamental cognitive processes was that improving these processes should ultimately improve general intellectual functioning. With respect to this aim, the correlational data from the present experiments with children revealed promising trends towards greater improvements on the tests of fundamental cognitive processes in those children in the training group with slower processing speed at the start of the intervention. This finding suggests that cognitive training may be even more effective at enhancing processing speed and other fundamental cognitive processes in children with intellectual impairments???who reportedly have slower processing speed than normal children. However, the extent to which training-related improvements in fundamental cognitive processes generalise to improvements in general cognitive functioning is unclear. That is, there is insufficient evidence that processing speed and other fundamental cognitive processes are causally related to intelligence. It is therefore essential that future cognitive training research is mindful of related developments within the intelligence and information processing literature.

Domestication has resulted in animals with broad variations between as well as within breeds, which allows for the selection and breeding of animals for preferred traits. This selection has affected both the genotypes and phenotypes of animals. In dogs, it has allowed for breeding for different purposes, such as companionship or the performance of specific tasks, e.g., herding, hunting, searching and protecting. Each of these types of working dogs has specific traits that are, in part, controlled by genes; however, genes are not solely responsible for the variations in the traits of an individual. The environment also plays a role, which has been studied in rodents and primates in recent decades. For instance, it has been shown that the amount of maternal care that a rat receives as a pup affects its temperament later in life; the more maternal care, i.e., licking, grooming and arched-back nursing (LG-ABN), that a rat receives, the more stress resistant, less reactive and more explorative it will be as an adult. However, the question is whether this is also true for dogs, and the investigation of how temperament in dogs is affected by environmental factors early in life is the main objective of this thesis. Three of the studies presented in this thesis focused on investigating the general parameters, particularly maternal care, that influences offspring behaviour to contribute to the understanding of temperament development in military working dogs. One of these studies concentrated on the environmental factors that influence dogs early in life, and the results indicated that some factors, such as parity, litter size and birth season, affect temperament later in life. Another study investigated how females take care of their young, and the results demonstrated that females consistently vary in their maternal style during the first three weeks postpartum and that this variation affects the temperament of the offspring. The third study focused on factors in the home environment, and the results showed that dogs approved through the evaluative temperament test were significantly associated with being hyperactive or restless and having difficulty settling down in the home environment. However, those dogs were also left home alone for more hours in a day than non-approved dogs. To be able to operate functionally, a military working dog needs to possess certain traits, or a certain temperament, and a vital characteristic is the way it responds to and copes with stress. This was investigated during an evaluative temperament test used to select dogs suitable for further training. Surprisingly, the results showed that the dogs approved for further training had significantly higher levels of salivary cortisol both before and after the test compared with the non-approved dogs. These findings may be of profound importance for understanding individual variations in behaviour and improving breeding schemes for working dogs. / För över 15 000 år sedan började våra anfäder avla på vargar och lade då grunden för den uppsjö av olika hundraser vi ser idag. Exakt hur den här processen såg ut, när eller vart den startade vet vi faktiskt inte med säkerhet, men att vargen/hunden var det första djur att påbörja en sådan förändring, det vet vi. Att aktivt välja ut och avla på önskvärda egenskaper påverkar och förändrar gradvis djuret. Den här förändringen styrs i hög grad av gener, vilket medför att ett djurs s.k. genotyp förändras. Den här förändringsprocessen, där ett djur gradvis anpassas till ett liv som tamdjur, kallas för domesticering och innebär inte bara att djuret förändras genetiskt, utan också att den ändrar utseende och beteende, dvs. djurets fenotyp ändras också. Det är därför vi bl. a. ser så många olika hundraser som vi gör idag, allt från en liten hårlös Chihuahua till en stor raggig St. Bernard. Alla är de hundar, men de ser väldigt olika ut och har delvis olika egenskaper eller temperament. Det medför att de passar till att göra olika saker och därför också kan vara till stor nytta i samhället i allt från sällskapshunden som kan lära sig leta kantareller, till olika typer av tjänstehundar. Bra ledarhundar åt synskadade, polishundar som söker försvunna människor och narkotika, och försvarsmaktens tjänstehundar som kan förhindra angrepp eller terrorverksamhet genom att leta efter t ex. bomber och vapen - alla kan i förlängningen innebära ökad livskvalité och räddade människoliv. Men för det krävs att hunden passar för jobbet. Det är både generna, arvet och olika miljöfaktorer i den tidiga uppväxten som avgör egenskaperna hos en individ. Det är något som har visat sig gälla till exempel för råttor och primater. Studier på råttor har exempelvis pekat på att mängden omvårdnad en råtta får som liten (t ex hur mycket mamman slickar sina barn) påverkar dess egenskaper som vuxen. Och att ju mer omvårdnad de fått, desto mer stresståliga, mindre nervösa och mer nyfikna blev de. Även i studier på människor pekar resultaten i samma riktning. Men gäller detta även för våra hundar? För att öka kunskapen om och förståelsen för hur tidiga erfarenheter påverkar temperament, stress och arbetsförmåga hos våra blivande tjänstehundar i försvarsmakten har därför en rad olika studier på området genomförts. Den här avhandlingen fokuserar således på att undersöka vilka generella tidiga erfarenheter och faktorer i den tidiga uppväxtmiljön som tycks kunna vara med och påverka temperamentet hos våra tjänstehundar. Specifikt undersöker den hur tikens omvårdnad påverkar vissa egenskaper. Avhandlingen undersöker vidare hur stresståliga våra hundar är och hur detta yttrar sig i samband med de lämplighets test som hundarna genomgår i syfte att bedöma vilka individer som bör gå vidare till fortsatt träning efter ett och ett halvt års ålder. Resultaten i en studie visar att de hundar som bedömts som lämpliga vid lämplighetstestet något oväntat uppvisade ett högre påslag av stresshormonet kortisol, och i en annan studie att lämpliga hundar bedömts vara hyperaktiva/rastlösa och ha vissa svårigheter att ta det lugnt i hemmiljö. Detta samtidigt som de uppvisade en önskvärd temperamentsprofil vid uttagningsprovet, vilket kan antyda att dessa hundar är mer flexibla och motståndskraftiga mot stress, vilket skulle kunna vara resultatet av en lyckad avel. Vidare visade resultaten att det finns generella faktorer i den tidiga uppväxtmiljön, såsom tikens tidigare erfarenhet av att vara mamma, kullstorlek och när på året kullen föds, som är med och påverkar olika egenskaper. Den visar också att tikarnas sätt att ta hand om sina valpar varierade men var konsekvent under den första omvårdnadstiden på tre veckor och att det finns en koppling mellan mammans omvårdnads-stil och hur deras valpar blir som vuxna. Sammantaget visar avhandlingen att det finns faktorer i den tidiga uppväxtmiljön som påverkar temperamentet senare i livet på våra tjänstehundar. / <p>The ISBN <strong>987</strong>-91-7685-945-2 in the thesis is incorrect. Correct ISBN is <strong>978</strong>-91-7685-945-2.</p>

Early reports of enhanced behavioral reactivity in isolation-reared rats attributed this syndrome to "isolation stress." In the studies reported here, this "isolation stress syndrome" was reliably obtained in adult rats reared from weaning in individual hanging metal cages. Such isolates showed behavioral and adrenocortical symptoms of profound fear during open-field testing, unlike group-housed controls or littermate isolates reared singly in plastic cages. Animals in hanging metal cages are never touched by human caretakers, whereas rats reared in plastic cages are picked up and put in clean cages twice weekly. Handling hanging-cage isolates twice weekly to model the handling associated with cage changes completely protected against this syndrome. Further, there was no hormonal, neurochemical or anatomical evidence of chronic stress even in hanging-cage isolates. Littermates housed in social groupings (three rats per plastic cage) also froze and defecated in the open field at rates comparable to hanging-cage isolates if they were the first animals to be tested from their social group cage. It is probable that odor cues from familiar cagemates in the open field protected socially reared animals tested subsequently from the same cage from this syndrome. It is concluded that isolates are not chronically stressed, and that rearing effects are the result of a complex interaction between prior handling, social experience and test conditions.

In infancy, the ability to tell the difference between two faces within a category (e.g., species, race) that is infrequently experienced declines from 6 to 9 months of age (Kelly et al., 2009, 2007; Pascalis et al., 2005; Pascalis, de Haan, & Nelson, 2002; Scott & Monesson, 2009). This decline in the ability to distinguish faces is known as "perceptual narrowing" and has recently been found to be absent when infants are given experience matching a face with an individual-level proper name between 6 to 9 months of age (Scott & Monesson, 2009). Additionally, individual-level experience between 6 and 9 months of age has led to neural changes at 9 months of age (Scott & Monesson, 2010). It is currently unclear whether brief, early experience between 6 and 9 months leads to sustained behavioral advantages and lasting neural changes. In order to answer these questions, the current study recruited and tested children who previously participated in a face training study when they were infants (Scott & Monesson, 2009, 2010). Findings revealed that individual-level experience with faces during the first year of life: 1) resulted in faster reaction time for faces outside of the trained category, and 2) led to more adult-like neural representations of faces outside of the trained category 3-4 years later. These results suggest that experience with individual-level learning in the first year of life is generalized to visually similar, but environmentally relevant face categories.

A gene x environment interaction exists in the expression of anxiety for both human and nonhuman primates, such that individuals who are carriers of the (s) allele of the serotonin transporter genotype ( 5-HTT LPR) and exposed to early life stress are more at risk for exhibiting anxiety. The hypothalamic-pituitary-adrenal (HPA) axis has also been implicated in anxiety disorders but the relationship between early life/genotype, HPA activity, and anxiety is not well understood. Further, studies linking the HPA axis to anxiety have relied on "point" samples (blood and salivary cortisol) which reflect moments in time rather than long-term activity. The purpose of this dissertation was three fold: (1) to examine anxious behavior in monkeys with different 5-HTT LPR genotypes and rearing environments across the first two years of life, (2) to compare long-term HPA activity (as measured with hair cortisol) with acute HPA activity (as measured with salivary cortisol) in the same period, and (3) to determine which measure of HPA activity predicts anxiety and/or mediates the rearing/genotype influences on anxious behavior. Infant rhesus monkeys ( Macaca mulatta , N=61) were mother-peer-reared (MPR, n=21), peer-reared (PR, n=20), or surrogate-peer-reared (SPR, n=20) for 8 months, then all relocated into a large social housing situation for the next 18 months. Monkeys were genotyped for 5-HTT LPR and hair and saliva samples were collected for cortisol analysis at months 6, 12, 18, and 24. Behavior was recorded twice per week per subject from 2-24 months and analyzed for the duration of anxiety, social play, and grooming. Regression analysis established predictors of these behaviors. Rearing condition and sex were significant predictors of anxiety across the two years, and HPA activity added significant predictive power in the first six months only. Mediation of the rearing/anxiety relationship by the HPA axis was not evident. Interestingly, hair (but not salivary) cortisol early in life was positively correlated with later anxious behavior. These findings demonstrate the detrimental effects of adverse early life experience on behavioral development and shed light on the interplay between environment, adrenocortical activity, and anxiety. They further demonstrate the usefulness of a long-term measure of HPA activity in predicting later behavior.

The aim of this study is to evaluate the outcome of adoptions and to study the gene-environment influences on psychiatric illness as well as sick-leave patterns. The material consists of 2 966 adopted persons born between 1917 and 1949, their 5 932 adoptive parents and 5 438 identified biological parents.Adopted persons had a higher incidence of personality disorders and substance abuse than non-adopted controls. Adopted men also had an increased incidence of neuroses. Adopted women had an increased sick-leave because of somatic complaints, especially upper respiratory tract infections and abdominal complaints of short duration. Somatization i.e. more than 2 sick-leaves/year because of somatic complaint together with nervous complaints was more frequent among adopted women. Women with somatization could be separated into 2 types according to the pattern of sick-leave. Type 1 ("high frequency") had frequent sick-leaves for psychiatric, abdominal and back complaints. They also had a high frequency of alcohol abuse. Type 2 ("diversiform") had more diverse complaints and had fewer sick-leaves because of nervous complaints.High frequency somatizers had biological fathers with teenage onset of criminality and frequent registrations for alcohol abuse. Diversiform somatizers had the same genetic background as adopted men with petty criminality or male limited alcoholism.No specific genetic influences on treated depression or substance abuse were found in this study. However, a non-specific vulnerability of the biological mother influenced on the risk of depression and substance abuse among adopted women.There were some indications that placement in the adoptive home between 6 and 12 months of age was associated with reactive neurotic depression in adult life. Otherwise early negative experiences in term of unstable placements before adoption did not significantly influence on psychiatric illness in adulthood.Affective disorders in the adoptive father were associated with treatment for depressions or substance abuse in the adoptee. Low social status in the part of the adoptive father increased the risk of somatization of both types in the adoptee. / <p>S. 1-80: sammanfattning, s. 81-236: 6 uppsatser</p> / digitalisering@umu

Ο νεογνικός χειρισμός, ένα πειραματικό μοντέλο πρώιμων εμπειριών, είναι γνωστό οτι επηρεάζει τη λειτουργία του άξονα υποθαλάμου-υπόφυσης-επινεφριδίων, βελτιώνοντας έτσι την προσαρμοστικότητα, την αντιμετώπιση του στρες, τις διανοητικές ικανότητες και γενικά τις διεργασίες του εγκεφάλου που σχετίζονται με την πλαστικότητα. Προηγούμενη μελέτη έχει δείξει οτι ο νεογνικός χειρισμός παρουσιάζει εκλεκτικές επιδράσεις στους υποδοχείς του N-μεθυλο-D-ασπαρτικού οξέος (NMDA) του διεγερτικού νευροδιαβιβαστή γλουταμινικό στον εγκέφαλο των επίμυων. Οι υποδοχείς του γλουταμινικού που διαμεσολαβούν την ταχεία συναπτική νευροδιαβίβαση στις διεγερτικές συνάψεις του κεντρικού νευρικού συστήματος είναι οι υποδοχείς του α-αμινο-3-υδροξυ-5-μεθυλο-ισοξαζολο-προπιονικού οξέος (AMPA) και είναι κρίσιμοι κατά τη νευρωνική ανάπτυξη, τη συναπτική πλαστικότητα και τη δομική αναδιαμόρφωση του εγκεφάλου. Συντίθενται από τέσσερις υπομονάδες, τις GluRA, GluRB, GluRC και GluRD, οι οποίες συνδυάζονται για να σχηματίσουν τετραμερή. Οι περισσότεροι υποδοχείς AMPA είναι ετεροτετραμερή, αποτελούμενα από τουλάχιστον δύο από τις αναφερθείσες υπομονάδες. Οι υποδοχείς AMPA που είναι διαβατοί στο ασβέστιο δεν περιέχουν την υπομονάδα GluRB, ενώ τόσο η υπομονάδα GluRA, όσο και η GluRB, παίζουν σημαντικό ρόλο στη συναπτική διακίνηση των υποδοχέων AMPA. Ο σκοπός της παρούσας εργασίας ήταν να ερευνηθεί κατά πόσο ο νεογνικός χειρισμός μπορεί να επιδρά στους υποδοχείς AMPA, εφόσον έχει δειχθεί οτι η σύνθεση των υπομονάδων και κατά συνέπεια και οι ιδιότητες των υποδοχέων AMPA στη σύναψη μεταβάλλονται από την αισθητική εμπειρία και κατά πόσο αυτή η επίδραση είναι εξαρτώμενη από το φύλο. Σύμφωνα με το παρόν πρωτόκολλο νεογνικού χειρισμού, κάθε νεογνό απομακρυνόταν από τη φωλιά για 15 λεπτά καθημερινά από την πρώτη μεταγεννητική ημέρα μέχρι τον απογαλακτισμό του τρεις εβδομάδες μετά. Η τεχνική του in situ υβριδισμού χρησιμοποιήθηκε για την εντόπιση και ποσοτικοποίηση της έκφρασης του mRNA της κάθε υπομονάδας. Η έκφραση των υπομονάδων του υποδοχέα AMPA μελετήθηκε σε συγκεκριμένες εγκεφαλικές περιοχές που εμπλέκονται στο συναίσθημα, στη μάθηση, στη μνήμη και στην αισθητική αντίληψη, όπως ο ιππόκαμπος, η αμυγδαλή και ο εγκεφαλικός φλοιός ενήλικων αρσενικών και θηλυκών επίμυων. Τα αποτελέσματα της έρευνας έδειξαν οτι ο νεογνικός χειρισμός προκάλεσε διαφορετικές και σε κάποιες περιπτώσεις φυλετικά διμορφικές μεταβολές στην έκφραση των υπομονάδων του υποδοχέα AMPA, με τρόπο ειδικό ανά υπομονάδα και περιοχή. Πιο συγκεκριμένα, τα ζώα που είχαν υποστεί νεογνικό χειρισμό, αρσενικά και θηλυκά, είχαν μειωμένα επίπεδα mRNA της GluRB και της GluRC στο ραχιαίο ιππόκαμπο και στο σωματαισθητικό φλοιό, συγκριτικά με τα ζώα χωρίς χειρισμό. Επιπλέον, τα επίπεδα mRNA της GluRC ήταν μειωμένα στην αμυγδαλή και στον προμετωπιαίο φλοιό και τα επίπεδα mRNA της GluRD ήταν μειωμένα στον κοιλιακό ιππόκαμπο αρσενικών και θηλυκών ζώων που είχαν υποστεί χειρισμό. Επιπροσθέτως, ο νεογνικός χειρισμός είχε φυλετικά διμορφικές επιδράσεις, αυξάνοντας τα επίπεδα mRNA της GluRA στο ραχιαίο ιππόκαμπο των αρσενικών ζώων και μειώνοντάς τα στα θηλυκά, καθώς και μειώνοντας τα επίπεδα mRNA της GluRΒ στον κοιλιακό ιππόκαμπο και στην αμυγδαλή μόνο των θηλυκών επίμυων. Οι μεταβολές στο mRNA των υποδοχέων AMPA θεωρούμε οτι συντελούνται μέσω επιγενετικής ρύθμισης λόγω του νεογνικού χειρισμού. Τα αποτελέσματα μας στο ραχιαίο ιππόκαμπο υποδεικνύουν ότι ο νεογνικός χειρισμός είναι πιθανό να προκαλεί επαγόμενη από την εμπειρία συναπτική ενδυνάμωση και αποδυνάμωση αρσενικών και θηλυκών ζώων αντίστοιχα, δεδομένων των αντίθετων μεταβολών που παρατηρούνται στα επίπεδα του mRNA της υπομονάδας GluRA στα δύο φύλα. Επιπλέον, η παρατηρούμενη μείωση της έκφρασης του mRNA της GluRB πιθανόν να οδηγεί σε μειωμένο αριθμό αδιάβατων στο ασβέστιο υποδοχέων AMPA που περιέχουν την υπομονάδα GluRB, οπότε ο νεογνικός χειρισμός μπορεί να προκαλεί μεταβολή στο φαινότυπο του υποδοχέα AMPA από αδιάβατο σε διαβατό στο ασβέστιο και τελικά αύξηση της πλαστικότητας της σύναψης στις περιοχές όπου παρατηρούνται οι μεταβολές. Συμπερασματικά, στην παρούσα μελέτη δείξαμε οτι οι υπομονάδες του υποδοχέα AMPA μεταβάλλονται από το νεογνικό χειρισμό, ένα μοντέλο πρώιμης εμπειρίας, στον εγκέφαλο ενήλικων επίμυων, με τρόπο ειδικό ανά υπομονάδα και ανά περιοχή και σε κάποιες περιπτώσεις φυλετικά διμορφικό. Αυτό σημαίνει οτι η γλουταμινεργική νευροδιαβίβαση μεταβάλλεται από μια πρώιμη εμπειρία. Αυτή η επίδραση του νεογνικού χειρισμού μπορεί να είναι ένας από τους παράγοντες που υπόκεινται της αυξημένης πλαστικότητας του εγκεφάλου των ζώων που έχουν υποστεί νεογνικό χειρισμό, η οποία εκδηλώνεται τόσο σε κυτταρικό επίπεδο όσο και στο συμπεριφορικό επίπεδο. / Neonatal handling, an experimental model of early life experiences, is known to affect the hypo¬thalamic-pituitary-adrenal axis function, thus increasing adaptability, coping with stress, cognitive abilities and in general brain plasticity-related pro¬cesses. Previous study has shown selective effects of neonatal handling on rat brain NMDA receptors. AMPA receptors (AMPARs) mediate fast synaptic trans¬mission at excitatory synapses in the CNS and are crucial during neuro¬nal development, synaptic plasticity and structural remodeling. AMPARs are composed of four types of subunits, designated as GluRA, GluRB, GluRC and GluRD, which combine to form tetramers. Most AMPARs are heterotetramerics, made of at least two of the four pro¬per subunits GluRA-D. AMPA receptors that are permeable to Ca2+ lack the GluRB subunit, while both GluRA and GluRB subunits have an important role in AMPAR trafficking towards the synapse. The present study addressed the question of whether neonatal handling might have an effect on AMRARs, since it has been shown that the subunit composition and thus the synaptic properties of AMPARs, changes in response to sensory experience, and whether this effect is gender-specific. According to the current neonatal handling pro¬tocol, each pup of a litter was removed from the nest for 15 min daily from the first postnatal day 1 (PND1) until weaning (PND22). In situ hybridization was used in order to localize and quantify subunit mRNA expression, with specific cDNA oligo¬nucleotides. AMPAR subunit expression was studied in specific brain regions that are involved in emotions, learning, memory and sensory perception, such as the hippo¬campus, cerebral cortex and amydgala of adult male and female rats. We found that neonatal handling caused differential and in cases sexually dimorphic changes in AMPA receptor subunit expression, depending on the brain region and the subunit. More specifically, neonatally handled animals, both males and females, had lower GluRB and GluRC mRNA levels in the dorsal hippocampus and the somatosensory cortex, compared to the non-handled. Moreover, GluRC mRNA levels were decreased in the amygdala and the prefrontal cortex and GluRD mRNA levels were decreased in the ventral hippocampus of handled animals of both sexes. Furthermore, neonatal handling had sexually dimorphic effects, increasing GluRA mRNA levels in the dorsal hippocampus of males while decreasing them in females, as well as decreasing GluRB mRNA levels in the ventral hippocampus and the amygdala only of the females. The observed changes in AMPA receptor mRNA levels are thought to occur via epigenetic regulation in response to neonatal handling. Our results in dorsal hippocampus suggest that neonatal handling may induce experience-dependent synaptic strengthening in males and weakening in females, due to the opposite changes observed in GluRA mRNA levels of the two sexes. Moreover, the observed decrease in GluRB mRNA expression most likely leads to reduced GluRB-containing calcium-impermeable AMPA receptors, therefore neonatal handling may cause a switch in AMPA receptor phenotype from calcium-impermeable to calcium-permeable AMPA receptors, and thus induce a higher synaptic plasticity in the regions where the changes are observed. In the present study we show that neonatal handling, an experimental model of early life experiences, induces changes in the AMPA receptor subunits expression in the adult rat brain that are region- and subunit-specific and in cases sexually dimorphic. These results demonstrate that glutamatergic transmission changes in response to an early experience. This effect of handling could be one of the factors underlying the increased plasticity of the brain of neonatally handled animals, which is manifested both at the cellular and at the behavioural/systemic level.

Adopted individuals have an increased risk for a variety of psychopathological disorders. Studies of the effects adoption in humans are difficult to perform because of the difficulty separating genetic risk and treatment effects. This is a developmental study investigating the effects of at birth adoption using a nonhuman primate model. Three experimental paradigms were used to assess maternal treatment, stress-related behavior, and physiology late in infancy and again later in life. Rhesus monkeys were reared for their first six months of life by either their biological mother or an unrelated, lactating adult female. Adoptions occurred immediately following birth. At six months of age, both groups were exposed to four, 4-day mother-infant separations. Behavioral observations and plasma stress hormones were used to compare the two group's responses to the separation stressor. Maternal treatments were also compared. In a second experiment performed about three years later when subjects were adolescents or young adults, an unfamiliar intruder was placed outside their home pen and stress-related behavioral responses were again measured. In the third experiment, adolescent subjects were allowed free access to a sweetened alcohol solution and daily alcohol consumption was measured across 8-10 weeks. Analyses showed that adopted subjects exhibited more behavior withdrawal and higher ACTH during the Acute and Chronic phases of the separation than infants reared by their biological mothers. This persisted when subjects were again tested with an intruder stressor 1-3 years later, with adopted subjects still showing more behavioral withdrawal during the Intruder Challenge stressor. Adopted subjects also differ in their relationship with their mother, showing more independence at an early age in non-stressful environments. Paradoxically, alcohol intake was lower in adolescents raised by an adoptive mother. Differences in maternal treatment and mismatches in temperament between the adopted mother and her infant are potential mechanisms that lead to the increased stress and anxiety in subjects raised by an adopted mother.