A biophysical model of synaptic plasticity and metaplasticity can account for the dynamics of the backward shift of hippocampal place fields.

Hippocampal place cells in the rat undergo experience-dependent changes when the rat runs stereotyped routes. One such change, the backward shift of the place field center of mass, has been linked by previous modeling efforts to spike-timing-dependent plasticity (STDP). However, these models did not account for the termination of the place field shift and they were based on an abstract implementation of STDP that ignores many of the features found in cortical plasticity. Here, instead of the abstract STDP model, we use a calcium-dependent plasticity (CaDP) learning rule that can account for many of the observed properties of cortical plasticity. We use the CaDP learning rule in combination with a model of metaplasticity to simulate place field dynamics. Without any major changes to the parameters of the original model, the present simulations account both for the initial rapid place field shift and for the subsequent slowing down of this shift. These results suggest that the CaDP model captures the essence of a general cortical mechanism of synaptic plasticity, which may underlie numerous forms of synaptic plasticity observed both in vivo and in vitro.

Short-Term Plasticity in a Computational Model of the Tail-Withdrawal Circuit in Aplysia.

The tail-withdrawal circuit of Aplysia provides a useful model system for investigating synaptic dynamics. Sensory neurons within the circuit manifest several forms of synaptic plasticity. Here, we developed a model of the circuit and investigated the ways in which depression (DEP) and potentiation (POT) contributed to information processing. DEP limited the amount of motor neuron activity that could be elicited by the monosynaptic pathway alone. POT within the monosynaptic pathway did not compensate for DEP. There was, however, a synergistic interaction between POT and the polysynaptic pathway. This synergism extended the dynamic range of the network, and the interplay between DEP and POT made the circuit responded preferentially to long-duration, low-frequency inputs.

Family Stability and Childhood Behavioral Outcomes: A Critical Review of the Literature

As the definition of what is considered a family changes in our society, the family unit itself continues to undergo changes. These changes can sometimes lead to decreased stability within the family unit. One of the greatest challenges facing those researching this phenomenon is the lack of consistency within the existing body of research surrounding what familial instability actually is (the definition). This critical review of the literature examines the current body of literature in order to identify what is known about family stability and its impact on adolescent behavior, as well as what gaps currently exist. This review focuses on definitions of family stability, current factors surrounding the stability of the family unit, and addresses the implications that the current body of literature presents.

Behavioral Outcomes of Home-Based Services for Children and Adolescents with Serious Emotional Disorders

The current study evaluates the effectiveness of an intensive home-based treatment program, Families First, on the behaviors of children and adolescents suffering from mental disorders and being at risk for out-ofi home placement. The sample included 85 youngsters and their families from a semi-rural community. The Diagnostic Interview for Children and Adolescents-Revised (DICA-R) was administered to the children, and the Child Behavior Checklist (CBCL) was completed by a parent at pretreatment and posttreatment. The families participated in a 4-6 week, intensive home intervention where crisis intervention, social support services, and needed psychological services were offered. The results indicated that both externalizing and internalizing behavior problems in youngsters with different diagnoses of mental disorders were significantly reduced at posttreatment as indicated by their CBCL scores. Furthermore, youngsters with a diagnosis of Oppositional Defiant Disorder seemed to benefit the most, as evidenced by the improved scores on most subscales of the CBCL. Youngsters with mood disorders and conduct disorders seemed to benefit in their most deficient areas, internalizing behavior problems and delinquent behaviors, respectively. Finally, after participating in Families First, more than half of the youngsters in the sample were able to stay home with their families

Food Insecurity and the Behavioral and Intellectual Development of Children: A Review of the Evidence

Background: Given that an alarming 1 in 5 children in the USA are at risk of hunger (1 in 3 among black and Latino children), and that 3.9 million households with children are food insecure, it is crucial to understand how household food insecurity (HFI) affects the present and future well-being of our children. Purpose: The objectives of this review article are to: (i) examine the association between HFI and child intellectual, behavioral and psycho-emotional development, controlling for socio-economic indicators; (ii) review the hypothesis that HFI is indeed a mediator of the relationship between poverty and poor child development outcomes; (iii) examine if the potential impact of HFI on caregivers’ mental health well-being mediates the relationship between HFI and child development outcomes. Methods: Pubmed search using the key words “food insecurity children.” For articles to be included they had to: (i) be based on studies measuring HFI using an experience-based scale, (ii) be peer reviewed, and (iii) include child intellectual, behavioral and/or socio-emotional development outcomes. Studies were also selected based on backward and forward Pubmed searches, and from the authors’ files. After reviewing the abstracts based on inclusion criteria a total of 26 studies were selected. Results: HFI represents not only a biological but also a psycho-emotional and developmental challenge to children exposed to it. Children exposed to HFI are more likely to internalize or externalize problems, as compared to children not exposed to HFI. This in turn is likely to translate into poor academic/cognitive performance and intellectual achievement later on in life. A pathway through which HFI may affect child development is possibly mediated by caregivers’ mental health status, especially parental stress and depression. Thus, HFI is likely to foster dysfunctional family environments. Conclusion: Findings indicate that food insecure households may require continued food assistance and psycho-emotional support until they transition to a “stable” food secure situation. This approach will require a much better integration of social policies and access to programs offering food assistance and mental health services to those in need. Findings also fully justify increased access of vulnerable children to programs that promote early in life improved nutrition as well as early psycho-social and cognitive stimulation opportunities.

The role of the bed nucleus of the stria terminalis in stress: A behavioral, neurophysiological and neuropharmacological study

During the fifty-five years since the origin of the modern concept of stress, a variety of neurochemical, physiological, behavioral and pathological data have been collected in order to define stress and catalogue the components of the stress response. Over the last twenty-five years, as interest in the neural mechanisms underlying the stress response grew, most of the studies have focused on the hypothalamus and major limbic structures such as the amygdala or on nuclei involved in neurochemical changes observed during stress. There are other CNS sites, such as the bed nucleus of the stria terminalis (BNST), that neuroanatomical and neurochemical studies suggest may be involved in stress, but these sites have rarely been studied. Four experiments were performed for this dissertation, the goal of which was to examine the BNST to determine its role in the regulation of the stress response. The first experiment demonstrated that electrical stimulation of BNST was sufficient to produce stress-like behaviors. The second experiment demonstrated that single BNST neurons altered their firing rate in response to both a noxious somatosensory stimulus such as tail pinch and electrical stimulation of the amygdala (AmygS). The third experiment showed that the opioid, cholinergic, and noradrenergic systems, three neurotransmitter systems implicated in the control of the stress response, were effective in altering the firing rate of BNST neurons. The fourth experiment demonstrated that the cholinergic effects were mediated via muscarinic receptors and showed that the effects of AmygS were not mediated via cholinergic pathways. Collectively, these findings provide a possible explanation for the nonspecificity in causation of stress and the invariability of the stress response and suggest a neurochemical basis for its pharmacological control. ^

Modulatory effects of bag cell peptides in {\it Aplysia}: Behavioral and electrophysiological studies

Reproductive hormones have effects on the nervous system not directly related to reproductive function. In the rat, for example, luteinizing hormone releasing hormone has dramatic effects on learning and memory. The present work attempts to examine the effects of reproductive hormones on non-reproductive behaviors and the neural loci and mechanisms underlying these effects in Aplysia, an animal whose behaviors, reproductive hormones and neural circuitry have been well characterized.^ In Aplysia, the neurosecretory bag cells release several peptides that are responsible for eliciting egg laying. The effects of these peptides on the defensive tail-siphon withdrawal reflex, as well as sensitization of this reflex, were examined. Sensitization, a simple form of nonassociative learning, refers to the behavioral enhancement of a response to a test stimulus after the presentation of a strong stimulus, that may last minutes (short-term) or days (long-term). An extract of the bag cells (BCE) inhibited the baseline siphon component of the tail-siphon withdrawal reflex and suppressed long-term, but not short-term, sensitization of the reflex. Preliminary experiments suggest that BCE also affects the tail component of the tail-siphon withdrawal reflex.^ To determine the neural mechanisms underlying the inhibition of the baseline reflex, electrophysiological studies were performed using an in vitro analogue of the tail-siphon withdrawal reflex to examine the ability of BCE, as well as the individual bag cell peptides (BCPs), to modulate the circuitry of the reflex. Bag cell extract attenuated the synaptic strength of the monosynaptic connections between tail sensory neurons and tail motor neurons. When individually applied only $\beta$-BCP produced a similar attenuation. This effect of $\beta$-BCP was not dependent on changes in duration of the presynaptic action potential.^ An in vitro analogue of long-term sensitization training was developed to examine the mechanisms by which the BCPs may affect long-term sensitization of the tail-siphon withdrawal reflex. This analogue exhibited both short- and long-term facilitation of the connections between the tail sensory and motor neurons.^ The results of these behavioral and electrophysiological experiments suggest that the BCPs inhibit the tail-siphon withdrawal reflex, at least in part, by modulating the synaptic strength of the connections between the sensory neurons and motor neurons underlying the reflex. One candidate for this effect is $\beta$-BCP. Thus, the peptides which elicit egg laying may also serve other functions such as the inhibition of defensive reflexes. In addition, these experiments raise the possibility that BCPs may exert a long lasting effect ($>$24 hr), suppressing long-term sensitization of the tail-siphon withdrawal reflex. ^

Anatomical organization of the memory underlying sensitization in the siphon-withdrawal reflex circuit of {\it Aplysia californica}

Previous studies have shown that short-term sensitization of the Aplysia siphon-withdrawal reflex circuit results in multiple sites of change in synaptic efficacy. In this dissertation I have used a realistic modeling approach (using an integrate-and-fire scheme), in conjunction with electrophysiological experiments, to evaluate the contribution of each site of plasticity to the sensitized response.^ This dissertation contains a detailed description of methodology for the construction of the model circuit, consisting of the LFS motor neurons and ten interneurons known to convey excitatory input to them. The model replicates closely the natural motor neuron firing response to a brief tactile stimulus.^ The various circuit elements have different roles for producing circuit output. For example, the sensory connections onto the motor neuron are important for the production of the phasic response, while the polysynaptic interneuronal connections are important for producing the tonic response.^ The multiple sites of plasticity that produce changes in circuit output also have specialized roles. Presynaptic facilitation of the sensory neuron to LFS connection enhances only the phasic component of the motor neuron firing response. The sensory neuron to interneuron connections primarily enhance the tonic component of the motor neuron firing response. Also, the L29 posttetanic potentiation and the L30 presynaptic inhibition primarily enhance the tonic component of the motor neuron firing response. Finally, the information content at the various sites of plasticity can shift with changes in stimulus intensity. This suggests that while the sites of plasticity encoding memory are fixed, the information content at these sites can be dynamic, shifting in anatomical location with changes in the intensity of the test stimulus.^ These sites of plasticity also produce specific changes in the behavioral response. Sensory-LFS plasticity selectively increases the amplitude of the behavioral response, and has no effect on the duration of the behavioral response. Interneuronal plasticity (L29 and L30) affects both the amplitude and duration of the behavioral response. Other sensory plasticity also affect both the amplitude and duration of the behavioral response, presumably by increasing the recruitment of the interneurons, which provide all of the effect on duration of the behavioral response. ^

Long-term synaptic facilitation of tail sensorimotor connections in {\it Aplysia\/}

Long-term sensitization in Aplysia is a well studied model for the examination of the cellular and molecules mechanisms of long-term memory. Several lines of evidence suggest long-term sensitization is mediated at least partially by long-term synaptic facilitation between the sensory and motor neurons. The sensitization training and one of its analogues, serotonin (5-HT), can induce long-term facilitation. In this study, another analogue to long-term sensitization training has been developed. Stimulation of peripheral nerves of pleural-pedal ganglia preparation induced long-term facilitation at both 24 hr and 48 hr. This is the first report that long-term facilitation in Aplysia persists for more than 24 hr, which is consistent with the observation that long-term sensitization lasts for more than one day. Thus, the data support the hypothesis that long-term facilitation is an important mechanism for long-term sensitization.^ One of the major differences between short-term and long-term facilitation is that long-term facilitation requires protein synthesis. Therefore, the effects of anisomycin, a protein synthesis inhibitor, on long-term facilitation was examined. Long-term facilitation induced by nerve stimulation was inhibited by 2 $\mu$M anisomycin, which inhibits $\sim$90% of protein synthesis. Nevertheless, at higher concentration (20 $\mu$M), anisomycin induced long-term facilitation by itself, which raises an interesting question about the function of anisomycin other than protein synthesis inhibition.^ Since protein synthesis is critical for long-term facilitation, a major goal is to identify and functionally characterize the molecules whose mRNA levels are altered during the formation of long-term facilitation. Behavioral training or its analogues (nerve stimulation and 5-HT) increases the level of mRNA of calmodulin (CaM). Thus, the role of Ca$\sp{2+}$-CaM-dependent protein kinase II (CaMKII), a major substrate of CaM, in long-term facilitation induced by nerve stimulation was examined. KN-62, a specific CaMKII inhibitor, did not block either the induction or the maintenance of long-term facilitation induced by nerve stimulation. These data indicate that CaMKII may not be involved in long-term facilitation. Another protein whose mRNA level of a molecule was increased by the behavioral training and the treatment of 5-HT is Aplysia tolloid/BMP-1-like protein 1 (apTBL-1). Tolloid in Drosophila and BMP-1 in human tissues are believed to be secreted as a metalloprotease to activate TGF-$\beta.$ Thus, the long-term effects of recombinant human TGF-$\beta1$ on synaptic strength were examined. Treatment of ganglia with TGF-$\beta1$ produced long-term facilitation, but not short-term or intermediate-term facilitation ($\le$4 hr). In addition, TGF-$\beta1$ and 5-HT were not additive in producing long-term facilitation, which indicates an interaction between two cascades. Moreover, 5-HT-induced facilitation (at both 24 hr and 48 hr) and nerve stimulation-induced facilitation (at 24 hr) were inhibited by TGF-$\beta$ sRII, a TGF-$\beta$ inhibitor. These results suggest that TGF-$\beta$ is part of the cascade of events underlying long-term sensitization, and also indicate that a signaling molecule used in development may also have functions in adult neuronal plasticity. ^

Behavioral and psychosocial factors associated with sexual risk in a population of crack cocaine users

The purpose of this dissertation was to examine the relationship between key psychosocial and behavioral components of the Transtheoretical Model and the Theory of Reasoned Action for sexual risk reduction in a population of crack cocaine smokers and sex workers, not in drug treatment. ^ The first study examined the results of an analysis of the association between two principal constructs in the Transtheoretical Model, the processes of change and the stages of change for condom use, in a high risk population. In the analysis of variance for all respondents, the overall F-test revealed that people in different stages have different levels of experiential process use, F(3,317) = 17.79, p = 0.0001 and different levels of behavioral process use, F(3,317) = 28.59, p = .0001. For the experiential processes, there was a significant difference between the precontemplation/contemplation stage, and both the action, and maintenance, stages.^ The second study explored the relationship between the Theory of Reasoned Action “beliefs” and the stages-of-change in the same population. In the analysis of variance for all participants, the results indicate that people in different stages did value the positive beliefs differently, F(3,502) = 15.38, p = .0001 but did not value the negative beliefs differently, F(3,502) = 2.08, p = .10. ^ The third study explored differences in stage-of-change by gender, partner type drug use, and HIV status. Three discriminant functions emerged, with a combined χ2(12) = 139.57, p = <.0001. The loading matrix of correlations between predictors and discriminant functions demonstrate that the strongest predictor for distinguishing between the precontemplation/contemplation stage and the preparation, action, and maintenance stages (first function) is partner type (.962). The loadings on the second discriminant function suggest that once partner type has been accounted for, ever having HIV/AIDS (.935) was the best predictor for distinguishing between the first three stages and the maintenance stage. ^ These studies demonstrate that behavioral change theories can contribute important insight to researchers and program planners attempting to alter HIV risk behavior in high-risk populations. ^

Behavioral effects of plasma tryptophan depletion in aggressive and nonaggressive men

Serotonin (5-HT) neurotransmission deficits have been implicated in impulsive aggression. A Trp-free beverage of amino acids competitively inhibits Trp uptake into the brain for 5-HT synthesis and also lowers endogenous plasma Trp for several hours. This has worsened mood and/or increased aggressive behavior, especially in hostile persons or those with histories of depression. In 24 community-recruited men (12 each with and without significant aggression histories), aggressive and impulsive behavior in the laboratory was assessed before and after plasma Trp depletion and Trp loading. In the aggression model, subjects were provoked by periodic subtractions of participation earnings, and these subtractions were blamed on a ficitious other participant. Aggression was measured as the responses the subject made to subtract money from his antagonist. Impulsiveness was operationalized as: (1) the choice of smaller reward after a shorter delay over having to wait longer to receive a larger reward, and (2) “false alarm” commission errors in a modified Continuous Performance Task, which represent a failure to inhibit responding to stimuli similar (but not identical) to target stimuli. Finally, plasma cortisol and Trp were measured under each condition immediately following a aggression testing session when subjects were highly provoked. I hypothesized that 5-HT may tonically modulate (inhibit) the hypothalmnic-pituitary-adrenal stress response, such that Trp depletion may enhance the cortisol response to high provocation in aggressive men. ^ Trp depletion had no effect in the laboratory tasks purported to measure impulsive behavior, and failed to cause increases in aggressive behavior under low provocation conditions. Under higher provocation, however, aggressive responses we re elevated under Trp-depleted conditions relative to Trp-loaded conditions in aggressive men, whereas the reverse was true in nonaggressive men. Cortisol levels nonsignificantly paralled the group differences in aggression under Trp-depleted and Trp-loaded conditions. Aggressive men achieved lower plasma Trp levels after Trp loading than did nonaggressive men, possibly due to heavy alcohol use histories. The high post-loading plasma Trp levels in nonaggressive men tended also to correlate with their aggressive responding rates, due perhaps to increases in other psychoactive Trp metabolites. ^

Signals underlying the induction and expression of long-term, injury-related plasticity in sensory neurons of Aplysia

An important goal in the study of long-term memory is to understand the signals that induce and maintain the underlying neural alterations. In Aplysia, long-term sensitization of defensive reflexes has been examined in depth as a simple model of memory. Extensive studies of sensory neurons (SNs) in Aplysia have led to a cellular and molecular model of long-term memory that has greatly influenced memory research. According to this model, induction of long-term memory in Aplysia depends upon serotonin (5-HT) release and subsequent activation of the cAMP-PKA pathway in SNs. The evidence supporting this model mainly came from studies of long-term synaptic facilitation (LTF) using dissociated (and therefore axotomized) cells growing in culture. However, studies in more intact preparations have produced complex and discrepant results. Because these SNs function as nociceptors, and display similar alterations (long-term hyperexcitability [LTH], LTF, and growth) in models of memory and nerve injury, this study examined the roles of 5-HT and the cAMP-PKA pathway in the induction and expression of long-term, injury-related LTH and LTF in Aplysia SNs. ^ The results presented here suggest that 5-HT is not a primary signal for inducing LTH (and perhaps LTF) in Aplysia SNs. Prolonged treatment with 5-HT failed to induce LTH of Aplysia SNs in either ganglia or dissociated-cell preparations. Treatment with a 5-HT antagonist, methiothepin, during noxious nerve stimulation failed to reduce 24 hr LTH. Furthermore, while 5-HT can induce LTF of SN synapses, this LTF appears to be an indirect effect of 5-HT on other cells. When neural activity was suppressed by elevating divalent cations or by using tetrodotoxin (TTX), 5-HT failed to induce LTF. Unlike LTF, LTH of the SNs could not be produced, even when 5-HT treatment occurred in normal artificial sea water (ASW), suggesting that LTH and LTF are likely to depend on different signals for induction. However, methiothepin reduced the later expression of LTH induced by nerve stimulation, suggesting that 5-HT contributes to the maintenance of LTH in Aplysia SNs.n of somata from the ganglion (which axotomizes SNs) or crushing peripheral n. ^ In summary, this study found that 5-HT and the cAMP-PKA pathway are not involved in the induction of long-term, injury-related LTH of Aplysia SNs, but persistent release of 5-HT and persistent PKA activity contribute to the maintenance of LTH induced by injury. (Abstract shortened by UMI.)^

Characterization of the interactions between two sites of plasticity engaged during eyelid conditioning

Here, we investigate the involvement of two sites of plasticity in the learning and expression of a simple associative motor behavior—the classically conditioned eyelid response. While previous studies clearly demonstrate that lesions of the anterior interpositus nucleus of the cerebellum abolish learned responses and prevent subsequent learning, studies investigating the effects of lesions of the cerebellar cortex on learning and retention have produced discrepant results. We complement ablative lesion studies of the cortex with the use of reversible, pharmacological blockade of cerebellar cortical transmission to investigate the role of the cerebellar cortex in eyelid conditioning. We demonstrate that both pharmacological blockade as well as focused ablative lesions of the cortex abolish timed responses and unmask responses with a fixed, short latency that are not displayed by the intact animal. Pharmacological blockade of cerebellar cortex output at various stages of acquisition and extinction reveals appropriate, learning dependent changes in the amplitude and probability of short latency responses during training. Acquisition of both short latency as well as timed responses is prevented by ablative lesions of the anterior lobe of the cerebellar cortex. These convergent results from technically distinct methods of removing the influence of the cerebellar cortex from conditioned behavior are consistent with the proposal that (1) eyelid conditioning engages two cerebellar sites of plasticity-one in the cortex and one in the anterior interpositus nucleus, (2) plasticity in the cerebellar cortex is necessary for proper response timing, (3) plasticity in the nucleus mediates the short latency responses unmasked by lesions of the cerebellar cortex, and (4) cerebellar cortical output is necessary for the induction of plasticity in the nucleus. ^

Development of dendritic tonic GABAergic inhibition regulates excitability and plasticity in CA1 pyramidal neurons

Synaptic plasticity rules change during development: while hippocampal synapses can be potentiated by a single action potential pairing protocol in young neurons, mature neurons require burst firing to induce synaptic potentiation. An essential component for spike timing-dependent plasticity is the backpropagating action potential (BAP). BAP along the dendrites can be modulated by morphology and ion channel composition, both of which change during late postnatal development. However it is unclear whether these dendritic changes can explain the developmental changes in synaptic plasticity induction rules. Here, we show that tonic GABAergic inhibition regulates dendritic action potential backpropagation in adolescent but not pre-adolescent CA1 pyramidal neurons. These developmental changes in tonic inhibition also altered the induction threshold for spike timing-dependent plasticity in adolescent neurons. This GABAergic regulatory effect upon backpropagation is restricted to distal regions of apical dendrites (>200 μm) and mediated by α5-containing GABA(A) receptors. Direct dendritic recordings demonstrate α5-mediated tonic GABA(A) currents in adolescent neurons which can modulate backpropagating action potentials. These developmental modulations in dendritic excitability could not be explained by concurrent changes in dendritic morphology. To explain our data, model simulations propose a distally-increasing or localized distal expression of dendritic α5 tonic inhibition in mature neurons. Overall, our results demonstrate that dendritic integration and plasticity in more mature dendrites are significantly altered by tonic α5 inhibition in a dendritic region-specific and developmentally-regulated manner.

Plasticity to wind is modular and genetically variable in Arabidopsis thaliana

Thigmomorphogenesis, the characteristic phenotypic changes by which plants react to mechanical stress, is a widespread and probably adaptive type of phenotypic plasticity. However, little is known about its genetic basis and population variation. Here, we examine genetic variation for thigmomorphogenesis within and among natural populations of the model system Arabidopsis thaliana. Offspring from 17 field-collected European populations was subjected to three levels of mechanical stress exerted by wind. Overall, plants were remarkably tolerant to mechanical stress. Even high wind speed did not significantly alter the correlation structure among phenotypic traits. However, wind significantly affected plant growth and phenology, and there was genetic variation for some aspects of plasticity to wind among A. thaliana populations. Our most interesting finding was that phenotypic traits were organized into three distinct and to a large degree statistically independent covariance modules associated with plant size, phenology, and growth form, respectively. These phenotypic modules differed in their responsiveness to wind, in the degree of genetic variability for plasticity, and in the extent to which plasticity affected fitness. It is likely, therefore, that thigmomorphogenesis in this species evolves quasi-independently in different phenotypic modules.