Psychology, Psychobiology

The purpose of this study was to determine whether behavioral contingencies or pharmacological exposure governs the development, loss and retention of tolerance to amphetamine-induced hypophagia in rats. In Experiment 1, rats that had developed tolerance by learning to suppress stereotypy that interfered with feeding from a bottle were divided into three groups to test the retention of tolerance. The Before group received injections of amphetamine (2.0 mg/kg) before access to milk, the After group received injections of amphetamine after access to milk, and the Saline group received injections of saline before access to milk. Both the After and Saline groups lost tolerance when later tested with amphetamine before milk tests. Thus, the loss of tolerance was not a function of drug withdrawal, because drug exposure remained constant in the After group. When milk reward was obtained noncontingently, tolerance was lost even though pharmacological exposure was maintained. Behavioral strategies that were learned while intoxicated were replaced with new learning when the contingencies were changed. Experiment 2 determined that tolerance loss was a function of new learning and not simply ingesting milk in the unintoxicated state. Bottle-fed tolerant rats were given amphetamine prior to intraoral feeding of milk during a retention interval. Subsequent testing with amphetamine in the bottle condition revealed that tolerance was lost. Because the cannula feeding condition does not require suppression of stereotypy, milk reward was available noncontingently in the intoxicated state and tolerance was lost even though drug exposure was maintained. In Experiment 3 rats were given chronic amphetamine injections and intraoral feeding. Subsequent tests with amphetamine and bottle feeding revealed that no tolerance developed. These results demonstrate that even when ingestion occurs in the intoxicated state, no tolerance develops if milk reward is available noncontingently. Animals that drank intraorally were not tolerant when tested in the bottle condition.

Psychoacoustic procedures were used to measure the heating thresholds of captive West Indian manatees under simultaneous masking conditions. Auditory detection thresholds of pulsed and non- pulsed pure tones, and complex sounds were measured against continuous white noise backgrounds through a series of forced-choice paradigms. Auditory thresholds as a function of signal intensity, center frequency, pulse repetition, spectral characteristics and bandwidth were measured. Resulting critical signal-to-noise ratios for pure tone measurements suggest manatees have relatively acute frequency filtering abilities compared with humans and other marine mammals. Signal characteristics such as repetition rate along with amplitude and frequency modulation may lower detection thresholds by providing temporal contrasts against aperiodic background noise. Thresholds for frequency modulated bandlimited signals were measured near or below background noise levels. Threshold tests using broadband signals, including a species specific call and samples of boat noise suggest that loudness summation across critical bands, as well as modulation of signals, can reduce the effects of masking observed with pure tones. To test a manatee's ability to localize sound sources in relation to its position in the water, a forced-choice egocentric (orientation) paradigm was used. The manatee demonstrated equal localization of sounds originating from the left or right side. While accuracy improved with higher frequencies the manatee demonstrated good overall localization of both low and higher frequency sounds, suggesting it may utilize both time of arrival cues and intensity difference cues for localizing brief sounds. The psychoacoustic data reveal some hearing abilities unique to manatees, as well as hearing phenomena similar to those observed among mammals and other vertebrates species. Manatees are well adapted for hearing and locating high frequency sounds in noisy shallow water habitats where physical boundary and near surface phenomena such as the Lloyd Mirror Effect can impede the propagation of low frequencies. Narrow critical bands and selective perception of pulsed signals may be adaptations for detecting species-specific vocalizations. Results indicate manatees can not effectively detect the low frequency sounds of approaching boats from safe enough distances to avoid collisions in the wild.

Two experiments are reported, both dealing with syllable affiliation of a consonant. The first experiment extends the work of Tuller and Kelso (1990) and was designed to capture the signatures of loss of stability in a dynamical system (enhanced fluctuations and critical slowing). An Articulograph device (Carstens Medizinelektronik GmbH.) was used to track the movements of the tongue tip, the lower lip, and the jaw in the midsagittal plane while the subjects spoke a VCC word in time to an auditory metronome at a slowly increasing rate. A clear transition occurred in the phonetics (VCC -> CVC) as judged by a phonetically trained listener, and the transition in phonetics corresponded to a change in the relative phase between the tongue tip and the lower lip and between the tongue tip and jaw. The transition was accompanied by both enhanced fluctuations and critical slowing for subjects who complied with the metronome. The second experiment examined syllable affiliation in natural English phrases with contrasting metrical structures. The phonemes /s/, /t/ and /k/, were used, and the tongue tip, tongue blade, and jaw were recorded by the Articulograph device. Consistent relative timing of the consonant movement in relation to vowel movement was observed, thus supporting the position that syllable affiliation is expressed as distinct phase values in natural speech as well as reiterated speech. In addition, the evidence supports the view that the syllable is an organizational unit of speech in English.

Recent studies have demonstrated that the strategy an individual uses to synchronize motor behavior (e.g. finger flexions) with externally delivered, periodic stimuli depends, in part, on the stimulus presentation rate (Mates, Muller, Radil, and Poppel, 1994; Engstrom, Kelso, and Holroyd, 1995). At rates slower than approximately 0.5 Hz, subjects typically exhibit a reactive-type coordination pattern where the response follows the stimulus by an order of magnitude consistent with typical response times (i.e. 150-250 milliseconds). At faster rates, however, subjects typically anticipate the impending stimulus in order to synchronize movement with it. In the present study, scalp electroencephalographic (EEG) signals (61 channels) were recorded during a sensorimotor task designed to investigate transitions from one coordination mode to another. We found that subjects exhibited a spontaneous transition from reactive to anticipatory behavior as the stimulus presentation rate increased past some critical frequency. A spatiotemporal analysis of the EEG signals accompanying this task revealed: (1) a widespread frequency component in the EEG matching that of both the stimulus and movement; (2) peak spectral power density over central and antero-central regions in both men and women during reactive behavior; (3) an additional bilaterally distributed frontal component at the most anterior portion of the scalp in men during anticipatory behavior; (4) an additional left fronto-central component which extended posteriorly toward antero-central regions in women during anticipatory behavior; (5) fluctuation enhancement in both the EEG spectral power density and the time lag ($\tau$) between the movement and stimulus accompanying the transition from reactive to anticipatory behavior; (6) that the spectral power density patterns obtained in the primary experimental condition (REACTIVE) were more similar in terms of their spatial distribution with a control condition in which subjects were asked to produce rhythmic movements without benefit of an external stimulus (MOTOR-ONLY) than with a control condition in which subjects passively watched a periodic visual stimulus (STIMULUS-ONLY); (7) that the spectral power density patterns obtained during reactive behavior in the primary experimental condition were more similar spatially to the MOTOR-ONLY condition than du ring anticipatory behavior; and finally (8) that the spectral power density patterns obtained during the experimental condition are not completely accounted for in terms of purely motor- or stimulus-related components. These results are discussed within a common framework of pattern formation instigated by dynamic instabilities in the human brain and behavior.

Autoimmunity may play a role in the pathology of autism. Previous studies have made comparisons between autistic individuals and genetically unrelated control subjects. These studies have provided useful information to support the autoimmune hypothesis. It is important, however, to analyze possible autoimmune responses in autistic patients and their genetically related non-autistic siblings. These comparisons are needed because environmental and genetic variables may contribute to the development of autoimmune responses. Moreover, if circulating autoantibodies to neural and glial proteins do contribute to pathology in the brains of autistic individuals, it should be possible to demonstrate that these antibodies bind to neural or glial proteins in vitro. The present study was performed to answer the following questions: First, do circulating antibodies to brain/somatic proteins exist in the serum of siblings, one of whom has been diagnosed with autism? Second, do differences exist in autoimmune reactions to brain somatic proteins in autistic and non-autistic siblings? Third, do circulating antibodies in the serum of these autistic and non-autistic siblings recognize and bind to neural proteins in situ? PAGE-SDS electrophoresis with subsequent Western blot experiments were performed to evaluate the presence of immune reactions to brain and somatic proteins in autistic individuals, genetically-related non-autistic siblings, and normal individuals. Results demonstrate that immunoglobulins to neural and somatic proteins exist in the serum of autistic individuals, as well as genetically related non-autistic siblings and normal individuals. Antibody reactions to specific brain proteins were higher in the serum of autistic individuals, as compared to genetically related non-autistic siblings. Immunohistochemical studies were performed to determine whether or not immunoglobulins in serum react with specific structures, such as neurons or glial cells, in human brain tissue. These studies confirmed that all serum types react with axonal proteins in at least two regions of the brain---the granular frontal neocortex (Brodmann's area 10 {BA10}) and the hippocampus. No tissue reactivity was observed in the anterior cingulate gyrus (BA24). These results support previous studies that suggest the following. (1) All individuals have autoimmune reactions to brain proteins, but that autistic patients have higher levels of immunoreactivity. (2) Within genetically related siblings, the occurrence of autism is related to higher levels of immunoreactivity to specific brain proteins, and (3) Immune reactions to axonal proteins may contribute to the CNS pathology in autistic syndrome.

The theta rhythm of the hippocampus, present in area CA1 of Ammon's horn and the dentate gyrus, is thought to serve a role in short-term memory processing. Rhythmically bursting cells of the medial septum projecting to the hippocampus are responsible for pacing theta. Further anatomical investigation of limbic-related circuitry in the rat, particularly connections of the medial septum and hippocampus, will lead to a better understanding of the pathways which influence the hippocampal EEG. Our first study examined single and collateral projections from the supramammillary nucleus to the medial septum and hippocampus, employing the retrograde fluorescent tracers FluoroGold and FluoroRuby. The supramammillary nucleus neurons we identified with collateral projections to the medial septum and hippocampus may be directly involved in generation of the theta rhythm. The second study examined single and collateral projections from the median raphe nucleus to the medial septum and hippocampus, employing the retrograde tracers FluoroGold and FluoroRuby. It has been proposed that the median raphe nucleus serves a direct role in desynchronization of the hippocampal EEG, or blockade of theta. The median raphe nucleus neurons we identified with collateral projections to the medial septum and hippocampus may be directly involved in the termination of theta, in turn modulating hippocampal memory processing. The third study examined afferent projections to the nucleus reuniens of the thalamus, employing the retrograde tracer FluoroGold, combined with a primary-antibody immunohistochemical procedure, in order to identify FluoroGold labeled cells by means of bright-field microscopy. RE afferents originate from widespread regions of the brain, providing multi-sensory and limbic input to RE. The fourth study examined efferents of the nucleus reuniens, employing the anterograde tracer PHA-L (Phaseolus vulgaris-leucoagglutinin). RE efferents terminated largely in regions of the telencephalon, and may influence working memory and sensorimotor systems. Investigations have linked the theta rhythm of the hippocampus to memory processing. The activity of the supramammillary nucleus, median raphe nucleus, and nucleus reuniens may influence the hippocampal EEG, particularly theta, and hence hippocampal mnemonic processing, by means of the pathways described in this dissertation.

Autism, characterized by disrupted social interaction and communication skills, and Attention Deficit Hyperactivity Disorder (ADHD), characterized by hyperactivity and inattention, are two neurodevelopmental disorders that have recently been linked to common dysfunctions in the frontal lobes and cerebellum. The present study was designed to evaluate the neonatal rat as an animal model for neurodevelopmental disorders. The behavior of rats with early Frontal (FR), Cerebellar (CB), or Frontal + Cerebellar (FR + CB) lesions, performed at either Post-natal Day 2 (PD 2) or 9 (PD 9), was evaluated with regard to activity, learning, social, and emotional behavior between the age of 3--31 days. In Experiment 1, 3 and 10-day-old pups were tested on their ability to habituate to a novel odor. FR lesions increased activity in 3-days-olds while CB, and FR + CB lesions disrupted odor habituation learning in 10-day-olds. In Experiment 2, 17-day-old pups were evaluated on activity in the open-field and ability to habituate to a novel environment. FR lesions resulted in increased locomotor activity while CB lesions resulted in increased grooming, a stereotypical behavior. Pups with PD 9 CB lesions also failed to habituate to the novel environment of the open-field. In Experiment 3, 24-day-old juveniles were evaluated on social behavior in the play test, as measured by frequency of pinning behavior. FR lesions increased levels of play behavior while CB lesions decreased play. In Experiment 4, 31-day-old juveniles were evaluated on emotionality in the elevated plus maze as measured by the number of distal open arms entries. Rats with CB lesions made twice as many distal open arm entries relative to the other lesioned groups; however, this result did not reach statistical significance. In conclusion, the results of the present study suggest that the effects of early frontal and cerebellar lesions can be dissociated on several different behavioral measures in young rats. Furthermore, neonatal rats with frontal and cerebellar lesions exhibit several behaviors during ontogeny that mimic those seen in children with ADHD and autism, such as hyperactivity and disrupted social interaction. The neonatal rat may thus prove to be a useful animal model for childhood neurodevelopmental disorders.

Previous studies conducted in this lab have shown that morphological changes occur in postsynaptic elements of brainstem gustatory relays during rat's postnatal life. Dendritic length and mitochondrial respiratory enzyme activity increase in the rostral nucleus of the solitary tract (NST) and in the caudal parabrachial nucleus (PBN). These increases are well-related to certain aspects of neurophysiological development in the NST and PBN. Other factors are known to contribute to the development of neurophysiological responses, such as synapse formation and myelination of axons. The present study examined developmental increases in protein P-38 immunoreactivity. Protein P-38 ("Synaptophysin") is a specific integral membrane protein found in small, clear synaptic vesicles. In addition, the time-course for myelination of central chorda tympani (CT) axons was investigated. Results demonstrate that P-38 immunoreactivity increases in the NST and PBN in a temporally-sequential manner during postnatal development. Reliable increases in P-38 immunoreactivity are observed between postnatal days 1 and 10 (P1-P10) in the rostral NST, whereas density of reaction products in the PBN increases from P11-P31. The time-course for myelination of chorda tympani (CT) axons within the medulla does not differ from the time-course for myelination of CT axons in the periphery. These studies confirm that both pre- and postsynaptic constituents of brainstem gustatory relays develop in a temporally-sequential manner. Relationships between these neurological changes and the ontogeny of adult-like taste-guided responses are discussed.