Steven F. Zornetzer

Age-related behavioral and neurobiological changes: A review with an emphasis on memory

This review focuses on age-related memory loss and its neurobiological correlates. A considerable body of evidence indicates that performance on tests of learning and memory declines with increasing age. Performance decrements have been documented in both human and animal studies employing tests of short- and long-term memory. In reviewing this voluminous literature, we have attempted to identify the critical factors accounting for the task-selective nature of these deficits. Important variables include task complexity, attention, and situational pacing requirements. Neurobiological changes associated with aging appear to be specific to particular anatomical regions and neurotransmitter systems. Most experimental interest has been directed toward the role of dopamine and acetylcholine in relation to memory deficits associated with aging. Norepinephrine has frequently been implicated in processes related to memory, including arousal, attention, and neural plasticity. In view of the role of norepinephrine in memory-related functions, we suggest that noradrenergic involvement in age-related memory dysfunction should receive more serious consideration.

Alcohol withdrawal in mice: Electroencephalographic and behavioral correlates ☆

Abstract Chronic bipolar electrodes were implanted in forebrain structures of mice including dorsal hippocampus, dorsal-frontal cortex, dorsal-lateral thalamus and septum. Two weeks after surgery, the mice were reduced to 85–90% of free-feeding weight, and physical dependence on alcohol was established by maintaining the mice on an alcohol-containing liquid diet for 6 days. A control group was pair-fed an identical liquid diet except sucrose was substituted isocalorically for alcohol. Following 6 days of consumption alcohol was withdrawn and the development of both EEG and behavioral sequelae of withdrawal was monitored for 6–8h. Only mice withdrawn from alcohol exhibited behavioral signs of withdrawal which included hyperactivity, severe tremor, ataxia, sudden sprawling movements, and clonic-tonic convulsions. No abnormal behavior and no abnormal EEG activity resulted from the withdrawal of the sucrose control diet. EEG recordings during withdrawal from alcohol, however, indicated a progressive development of widespread neural epileptiform activity beginning with EEG slowing and increased amplitudes, followed by single spike events and often leading to sustained epileptic seizure discharge. Similar abnormal EEG patterns were observed throughout the forebrain including cortex, thalamus, hippocampus and septal area. The development of abnormal EEG activity was more severe during the second alcohol withdrawal period following 4 days of alcohol exposure than during the first alcohol withdrawal period following 6 days of alcohol exposure. It is hypothesized that the widespread forebrain epileptiform activity originates in, or is organized from, a central pacemaking region such as midline thalamus or reticular formation.

Modulation of Learning and Memory: Effects of Drugs Influencing Neurotransmitters

Drugs have been utilized for many years as experimental tools in the analysis of the biological mechanisms underlying behavior. An assumption implicit in this approach is that an assessment of the actions of various drugs on behavior, coupled with knowledge of mechanisms of drug action, will provide important information concerning the neurobiological bases of behavior.

Alcohol withdrawal syndrome in rats: Neural and behavioral correlates

Abstract Rats were chronically implanted with electrodes in the ventral hippocampus, amygdala and anterior cortex and maintained on liquid diets as their only source of calories and fluid for 15 days. The diet consisted of 35–40% of the calories in the form of ethanol while a control group was pair-fed identical diets with sucrose isocalorically substituted for ethanol. On the sixteenth day the diets were removed and electrographic activity and behavior were simulataneously observed for 8–10 hr. Withdrawal symptoms were observed beginning 2–4 hr following alcohol abstinence and included tail-stiffening, tremors, severe ataxia and auditory-induced convulsions. EEG epileptiform activity was observed and initially consisted of transient spike events, which usually became progressively organized into brief spike burst sor sustained paroxysmal activity. The results suggested that cortical bioelecric activity may not play a primary role in the genesis of behavioral hyperexcitability during alcohol withdrawal. The utility of the method of combined observations of neural bioelectric activity and behavior for the delineation of the neural substrates of alcohol withdrawal symptoms was discussed.

Electrolytic lesions of various hippocampal subfields in the mouse: differential effects on short- and long-term memory.

Small bilateral electrolytic lesions of various hippocampal subfields of mice resulted in short-term memory (STM) and long-term memory (LTM) deficits in a one-trial inhibitory avoidance task. Lesions not involving the dentate gyrus (i.e., primarily CA1) resulted in STM impairment. Lesions including the dentate gyrus bilaterally resulted in both STM and LTM deficits. These data are discussed in the context of different functional roles for various hippocampal subfields in STM and LTM.

The hippocampus and retrograde amnesia: localization of some positive and negative memory disruptive sites.

Electrical stimulation of the hippocampus was used to produce retrograde amnesia in mice. Both subthreshold stimulation and suprathreshold stimulation for the production of hippocampal afterdischarge activity resulted in amnesia for an inhibitory avoidance task. The magnitude of amnesia differed, however, with the two types of stimulation. Histological analysis of the electrode placements indicated that the effective amnesia-producing sites were located in the area dentata of the hippocampus. Electrode placements not bilaterally symmetrical in this area failed to produce amnesia. The role of bilateral symmetry in brain malfunction induced by various experimental treatments is discussed.

Memory and postsynaptic cholinergic receptors in aging mice

Significant retention deficits were observed on passive avoidance tasks (step-down and step-through) in 15-, 20-, and 25-month-old male C57BL/6 mice compared with 4- and 8-month-old mice. In contrast, cholinergic muscarinic receptor binding ( [3H]quinuclidinyl benzilate) in cerebral cortex, striatum, hippocampus, and cerebellum in these same animals revealed no difference in this 4- to 25-month age range. In a separate comparison of 4- and 29-month-old female mice, [3H]QNB binding was significantly decreased in the older group in cerebral cortex, hippocampus, and striatum. Environmental enrichment, compared with an impoverished environment, significantly improved retention in mice on 24-hr step-down performance but affected QNB binding only minimally (6-7% decrease of QNB binding in cerebral cortex and hippocampus). Benzodiazepine ( [3H]flunitrazepam) receptor binding was significantly (12-15%) decreased in 29-month-old mice compared with 4-month-old mice in the cerebral cortex, hippocampus, cerebellum, and brain stem.

The locus coeruleus: Its possible role in memory consolidation

Abstract Three experiments were done looking at the effects on memory of discrete electrolytic lesions in the locus coeruleus of mice. In Experiment 1 mice received electrolytic lesions of the locus coeruleus immediately following training on the 1 trial inhibitory avoidance step-through task. Retention of this response, measured 48 hr later was normal, suggesting that locus coeruleus lesions per se do not interfere with the performance of this rather simple response. In Experiments 2 and 3 mice were treated exactly as in Experiment 1 except that a transcorneal ECS was administered 40 hr or 7 days after initial training and locus coeruleus lesions. Mice with locus coeruleus lesions were amnesic following a 40 hr delayed ECS treatment when tested either 8 hr or 24 hr after ECS. Mice with locus coeruleus lesions were not amnesic following a 7 day delayed ECS. These data are interpreted to suggest that the locus coeruleus is normally involved in the temporal delineation of the susceptibility period of newly formed memory. A malfunction of the locus coeruleus can result in a profound extension of the normal susceptibility period of newly formed memory to ECS produced amnesia.

Locus coeruleus and labile memory

Abstract Memory lability is defined as the period of time recently-formed memory remains susceptible to experimental modification. Electrolytic lesions delivered through chronic indwelling electrodes to the locus coeruleus (LC) complex of mice, made shortly after learning, resulted in an extension of memory lability. Mice with unilateral, but not bilateral LC damage became amnesic following electroconvulsive shock (ECS) administered 7 days (168 hr) after memory formation. ECS had no effect on memory in LC-lesioned mice when administered 14 days following training. In a second experiment, the temporal relationship between time of memory formation and time of LC damage was found to be critical to the occurrence of this extended period of lability. In a third experiment, we tested the possibility that prolonged trace lability was the result of weaker memory formation as reflected by decreased persistence (i.e. faster forgetting) of the memory. The results indicated equal rates of forgetting for normal and LC-lesioned mice. Present results support the hypothesis that the locus coeruleus complex normally plays an important role in delimiting the time-course of initially labile stages of memory. By inference, these data suggest further that such a delimiting function of the locus coeruleus is mediated through its noradrenergic modulation of other brain regions.

Age-related memory deficits in Swiss mice

The performance of young (3–5 months) and aged (20–21 months) Swiss mice on a step-down passive-avoidance task was compared in two separate experimental paradigms. Preliminary shock sensitivity testing demonstrated that response thresholds did not differ significantly between young and aged mice. Aged mice trained on a single-trial step-down procedure demonstrated significant retention deficits compared to young mice at a 24-hr training-testing interval, but not a 2-hr interval. Separate groups of mice were trained to a 180-sec criterion of avoidance and tested daily for retention over 10 days following acquisition training. Aged mice tended to step-down sooner than young animals. These data suggest age-related retention deficits in the Swiss mouse for step-down passive avoidance without significant alterations in shock sensitivity.