Rainer K.W. Schwarting

THE UNILATERAL 6-HYDROXYDOPAMINE LESION MODEL IN BEHAVIORAL BRAIN RESEARCH. ANALYSIS OF FUNCTIONAL DEFICITS, RECOVERY AND TREATMENTS

Lesions with the neurotoxin 6-hydroxydopamine (6-OHDA) have provided an important tool to study dopamine neurons in the brain. The most common version of such lesions is the unilateral one where the toxin is placed in the area of mesencephalic dopamine cell bodies or their ascending fibers. This approach leads to a lateralized destruction of mesencephalic dopamine neurons and to a lateralized loss of striatal dopamine innervation. Such lesions have contributed substantially to neuroscientific knowledge both, at the basic and clinical level. Physiologically, they have been used to clarify the neuroanatomy, neurochemistry, and electrophysiology of mesencephalic DA neurons and their relationships with the basal ganglia; the relevant findings have been summarized in a previous review (Schwarting, R.K.W. and Huston, J.P. (1996) Unilateral 6-hydroxydopamine lesions of meso-striatal dopamine neurons and their physiological sequelae, Progress in Neurobiology 49, 215-266). Furthermore, 6-OHDA lesions have been used extensively to investigate the role of these dopamine neurons with respect to behavior, to examine the brains capacity to recover from or compensate for specific neurochemical depletions, and to investigate the promotive effects of experimental and clinical approaches which are relevant for the treatment of Parkinsons disease. These findings are summarized here, including the spectrum of behavioral deficits (turning, sensory neglect, etc.), functional recovery and its possible mechanisms, the behavioral effects of widely used pharmacological challenges (amphetamines, apomorphine, selective receptor agonists, L-DOPA), and the effects of treatments which can promote recovery (like neuropeptides, neurotrophins, and grafts).

UNILATERAL 6-HYDROXYDOPAMINE LESIONS OF MESO-STRIATAL DOPAMINE NEURONS AND THEIR PHYSIOLOGICAL SEQUELAE

One of the primary approaches in experimental brain research is to investigate the effects of specific destruction of its parts. Here, several neurotoxins are available which can be used to eliminate neurons of a certain neurochemical type or family. With respect to the study of dopamine neurons in the brain, especially within the basal ganglia, the neurotoxin 6-hydroxydopamine (6-OHDA) provides an important tool. The most common version of lesion induced with this toxin is the unilateral lesion placed in the area of mesencephalic dopamine somata or their ascending fibers, which leads to a lateralized loss of striatal dopamine. This approach has contributed to neuroscientific knowledge at the basic and clinical levels, since it has been used to clarify the neuroanatomy, neurochemistry, and electrophysiology of mesencephalic dopamine neurons and their relationships with the basal ganglia. Furthermore, unilateral 6-OHDA lesions have been used to investigate the role of these dopamine neurons with respect to behavior, and to examine the brains capacity to recover from or compensate for specific neurochemical depletions. Finally, in clinically-oriented research, the lesion has been used to model aspects of Parkinsons disease, a human neurodegenerative disease which is neuronally characterized by a severe loss of the meso-striatal dopamine neurons. In the present review, which is the first of two, the lesions effects on physiological parameters are being dealt with, including histological manifestations, effects on dopaminergic measures, other neurotransmitters (e.g. GABA, acetylcholine, glutamate), neuromodulators (e.g. neuropeptides, neurotrophins), electrophysiological activity, and measures of energy consumption. The findings are being discussed especially in relation to time after lesion and in relation to lesion severeness, that is, the differential role of total versus partial depletions of dopamine and the possible mechanisms of compensation. Finally, the advantages and possible drawbacks of such a lateralized lesion model are discussed.

Behavioral phenotyping of the MPTP mouse model of Parkinson's disease

In mice, the systemical or intracranial application of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can lead to severe damage to the nigrostriatal dopaminergic system. This can result in a variety of symptoms concerning motor control resembling those in human Parkinsons disease, such as akinesia, rigidity, tremor, gait and posture disturbances. The aim of this work is to review a variety of behavioral paradigms for these and other symptoms, which have been used to characterize behavioral changes in mice after MPTP treatment. Main results are summarized, and general influential factors as well as potential problems in the experimental procedures are discussed, which should be taken into account when conducting behavioral analyses in mice with parkinsonian symptoms. Since there is reliable evidence (e.g. from strain comparisons) that the susceptibility of the nigrostriatal pathway to neurodegeneration is probably genetically influenced, relevant genes can be expected to be identified in the future. Therefore, the points discussed here will be useful not only for further applications in the MPTP mouse model, but also more generally for the behavioral characterization of future mouse models of PD, e.g. mice with a manipulation of genes relevant to the function of the basal ganglia.

Animal models of human psychopathology based on individual differences in novelty-seeking and anxiety

The role of individual factors in behavioural neuroscience is an important, but still neglected area of research. The present review aims to give, first, an outline of the most elaborated theory on animal behaviour, and second, an overview of systematic approaches of historic and present animal models of human psychopathology based on individual differences. This overview will be focused on animal models of unselected subjects (i.e. natural variance of a specific behaviour within a given population) and selected breeding for a specific behaviour. Accordingly, an outline of the personality model from Gray and McNaughton of individual behaviour in animals is given first. Then, a comprehensive overview of past and current animal models in novelty-seeking (i.e. psychomotor activation and exploration behaviour) based on systematic individual differences and its relationship to addiction is presented. Third, this will be followed by a comprehensive overview of individual differences in previous and present animal models for anxiety. Finally, critical aspects of such approaches in animal research are discussed, and suggestions are given where to go from here.

Expectancies as core features of mental disorders.

Purpose of review Expectancies are core features of mental disorders, and change in expectations is therefore one of the core mechanisms of treatment in psychiatry. We aim to improve our understanding of expectancies by summarizing factors that contribute to their development, persistence, and modification. We pay particular attention to the issue of persistence of expectancies despite experiences that contradict them. Recent findings Based on recent research findings, we propose a new model for expectation persistence and expectation change. When expectations are established, effects are evident in neural and other biological systems, for example, via anticipatory reactions, different biological reactions to expected versus unexpected stimuli, etc. Psychological ‘immunization’ and ‘assimilation’, implicit self-confirming processes, and stability of biological processes help us to better understand why expectancies persist even in the presence of expectation violations. Summary Learning theory, attentional processes, social influences, and biological determinants contribute to the development, persistence, and modification of expectancies. Psychological interventions should focus on optimizing expectation violation to achieve optimal treatment outcome and to avoid treatment failures.

On the relationships between ultrasonic calling and anxiety-related behavior in rats

In the present review, the phenomenon of ultrasonic vocalization in rats will be outlined, including the three classes of vocalizations, namely 40-kHz calls of pups, and 22- and 50-kHz calls of juvenile and adult rats, their general relevance to behavioral neuroscience, and their special relevance to research on anxiety, fear, and defense mechanisms. Here, the emphasis will be placed on 40- and 22-kHz calls, since they are typical for various situations with aversive properties. Among other topics, we will discuss whether such behavioral signals can index a certain affective state, and how these signals can be used in social neuroscience, especially with respect to communication. Furthermore, we will address the phenomenon of inter-individual variability in ultrasonic calling and what we currently know about the mechanisms, which may determine such variability. Finally, we will address the current knowledge on the neural and pharmacological mechanisms underlying 22-kHz ultrasonic vocalization, which show a substantial overlap with mechanisms known from other research on fear and anxiety, such as those involving the periaqueductal gray or the amygdala.

Activation of limbic system structures by replay of ultrasonic vocalization in rats

Abstract Since the first observation of ultrasonic vocalizations in rats, several hypotheses have been proposed regarding a possible function of such calls as echolocation, temperature regulation and others. Today, however, it is well-established that ultrasonic vocalizations in rats serve as important social signals. Rat behavioral and neuronal responses to 22 kHz calls indicate that this call type serves as an alarm call. Although 22 kHz calls are not innately recognized as alarm calls, they can reach alarm signal value as a consequence of associative learning, which is facilitated by a biological preparedness to associate 22 kHz calls with aversive events. The perirhinal cortex might be at least part of the “neural template” responsible for such a biological preparedness. On the other hand, behavioral and neuronal responses to 50 kHz calls indicate that this call type serves as a contact call. Social approach displayed in response to 50 kHz calls is paralleled by an activation of frontal cortex and the nucleus accumbens, which might be related to the appetitive value of 50 kHz calls.

Rodent models of serial reaction time tasks and their implementation in neurobiological research

Since the late eighties of the last century, when the so-called serial reaction time (SRT) task was first presented, analysis of sequential learning and performance has developed into a prosperous area of neurocognitive research in human subjects and non-human primates. In more recent years, rodent implementations of SRT tasks have become available, which will be summarized here and discussed with respect to their advantages, but also to their methodological and theoretical drawbacks. Then, a review of new neurobiological findings with such rodent tasks will be provided, that will be embedded into the existing theoretical framework, originally obtained from the work with primate species. Among others, this review will show that rodent SRT tasks allow actualizing and thus, studying many psychological features of human sequential tasks, for example, cognitive complexity of sequences. Since these rodent tasks can be used for a number of neuronal analyses, it is assumed that they will provide important insights for the neural mechanisms underlying such cognitive functions.

Environmental and Pharmacological Modulation of Amphetamine- Induced 50-kHz Ultrasonic Vocalizations in Rats.

Rats emit high-frequency 50-kHz ultrasonic vocalizations (USV) in appetitive situations like social interactions. Drugs of abuse are probably the most potent non-social elicitors of 50-kHz USV, possibly reflecting their euphorigenic properties. Psychostimulants induce the strongest elevation in 50-kHz USV emission, particularly amphetamine (AMPH), either when applied systemically or locally into the nucleus accumbens (Nacc). Emission of AMPH-induced 50-kHz USV depends on test context, such as the presence of conspecifics, and can be manipulated pharmacologically by targeting major neurotransmitter systems, including dopamine (DA), noradrenaline (NA), and serotonin (5-HT), but also protein kinase C (PKC) signaling. Several D1 and D2 receptor antagonists, as well as typical and atypical antipsychotics block the AMPH-induced elevation in 50-kHz USV. Inhibiting D1 and D2 receptors in the Nacc abolishes AMPH-induced 50-kHz USV, indicating a key role for this brain area. NA neurotransmission also regulates AMPH-induced 50-kHz USV emission given that α1 receptor antagonists and α2 receptor agonists exert attenuating effects. Supporting the involvement of the 5-HT system, AMPH-induced 50-kHz USV are attenuated by 5-HT2C receptor activation, whereas 5-HT2C receptor antagonism leads to the opposite effect. Finally, treatment with lithium, tamoxifen, and myricitrin was all found to result in a complete abolishment of the AMPH-induced increase in 50-kHz USV, suggesting the involvement of PKC signaling. Neurotransmitter systems involved in AMPH-induced 50-kHz USV emission only partially overlap with other AMPH-induced behaviors like hyperlocomotion. The validity of AMPH-induced 50-kHz USV as a preclinical model for neuropsychiatric disorders is discussed, particularly with relevance to altered drive and mood seen in bipolar disorder.

APP transgenic mice: the effect of active and passive immunotherapy in cognitive tasks.

Various immunotherapy strategies for APP transgenic mice have emerged in recent years. Specifically, active immunization with beta-amyloid (A beta) or passive immunization with anti-A beta-antibodies in APP transgenic mice has appeared most promising. Recent studies have shown that treatment of APP transgenic mice either with A beta(40/42) or A beta-specific antibodies can have beneficial effects in cognitive tasks. Active as well as passive immunization have been shown to affect spatial, non-spatial, emotional and object-related learning and memory. Such effects can be observed when treatments are applied prophylactically (before apparent A beta pathology) or therapeutically (after the development of A beta pathology) in APP transgenic mice. This review focuses on such cognitive outcomes of different active and passive immunization strategies in APP transgenic mice.