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Adult animal studies of concurrent zinc deficiency and behavior typically employed a severe deprivation and demonstrated lethargy and poorer behavioral performance (Gordon et al. l 982, Hesse et al. l 979). Few studies of the concurrent effects of zinc deficiency on behavior of immature animals were located.
Strobel and Sandstead (1984) provided a preliminary report of studies using severe concurrent zinc deficiency (< 1D g Zn/g) in nursing and juvenile rhesus monkeys. Zinc-deprived nursing infants were more protected by their dams and more sensitive to maternal separation. Zinc-deprived juveniles had difficulties with retention of previously learned visual discrimination problems and with acquisition of more difficult problems of this type. Macapinlac et al. l 1967) induced a dietary zinc deficiency syndrome in immature squirrel monkeys and described behavioral changes but did not include formal behavioral assessments.
We recently reported a study of concurrent zinc deprivation on behavioral performance in juvenile rhesus monkeys (25-30 mo of age, sexual maturation 36-48 mo of age) using a crossover design (Golub et al. 1994) (see Table 2). A 2-D g Zn/g diet (moderate zinc deprivation) was fed over a 15-wk period and led to lowered plasma zinc levels but no inhibition of growth. The zinc deprivation period was compared with similar zinc-adequate (50 D g Zn/g) diet period that either preceded or followed it in two different subgroups. Spontaneous motor activity was lower during the zinc deprivation period. Performance of a visual attention task (the continuous performance test) was also poorer during the zinc deprivation period. A short-term memory task (delayed spatial alternation, 0-, 3- and 5-s delays) was affected only at the intermediate 3-s delay. It should be noted that behavioral effects were detected as changes from individual baselines and often represented a failure to improve rather than a deterioration of performance.
Over a period of several years we conducted a series of studies of rhesus monkeys deprived continuously of zinc (marginal deprivation) from conception through adolescence (see Table 2). The studies included behavioral assessments at several stages of maturation. This experimental paradigm provides concurrent deprivation preceded by developmental deprivation during the period of rapid brain growth, the most probable situation in human-malnourished populations. However, this paradigm does not allow separation of concurrent and critical periods effects.
Transient growth retardation was seen in infancy and adolescence, but the growth, health and maturation of the animals were not grossly affected. Hypotonia, recorded at birth, may have been secondary to previously documented effects of zinc deficiency on labor and delivery. Results of the behavioral assessments from this study are outlined in Table 2. In general hypoactivity-reduced environmental responsiveness was characteristic of the young monkeys. Effects on performance of a cognitive task (visual discrimination learning and reversal) seemed more marked during the adolescent than the juvenile period. Performance of a spatial-delayed response task was improved, a finding that is consistent with reduced activity. Hypogeusia and altered preference for novel foods were demonstrated, but reduced food intake was not recorded at any time in the study.
Adult studies of behavioral effects of concurrent zinc deprivation include observations (Sandstead et al. 1981) and, more recently, structured tests of cognitive function (Penland 1991, Tucker and Sandstead 1984, Wallwork et al. 1982). Several behavioral measures, including some reflecting memory, were found to be sensitive to zinc deprivation, but data were too limited to draw firm conclusions. Adult studies may be relevant to concurrent effects in children; there is no reason a priori to assume that concurrent effects in children would be fundamentally different from those seen adults.
There are no strictly experimental studies of zinc deficiency and behavior in infants or children. Two studies with zinc supplementation in school-age children were done by the same research group, one in Canada and one in Guatemala. Both studies supplemented 6 to 7-y-old children with 10 mg Zn/d. In the Canadian study, boys were selected for low height-for-age centiles and received either placebo or supplement for 12 mo (Gibson et al. 1989). In the Guatemalan study, poorly nourished children (male and female) were randomly assigned to receive placebo or the zinc supplement for 25 d (Cavan et al. 1 993a). Both studies used multiple indices of zinc status and found a positive response to supplement in terms of height-for-age (Ontario) and body composition (Guatemala). In both studies, supplemented children failed to show improvement on subtests of the Detroit Test of Learning Abilities selected to assess attention.
A number of behavioral assessments (standardized cognitive testing, observation and teacher ratings of classroom behavior, activity level and social and emotional measures) were determined in school children (age 7-10) from an Egyptian village where the traditional diet had a low level of bioavailable zinc (Wachs et al. 1995). There was a significant correlation between dietary zinc and girls' attention-seeking behavior in the classroom.
Dietary zinc, along with six other nutrients, provided significant prediction of this behavior in multivariate regressions. Dietary zinc in combination with five other nutrient variables also significantly predicted boys' activity level in multiple regressions.
Unfortunately, behavior has not as yet been studied in connection with zinc status or zinc intake of infants and adolescents. These groups are at higher risk of zinc deficiency due to rapid growth than are school-age 15 to 12-y-old) children.
A major emphasis in developmental zinc deprivation research has been on the role of zinc-dependent enzymes in critical cell replication processes and consequent effects on brain growth. Indeed, linear growth is sensitive to zinc deprivation, age groups experiencing rapid growth are most susceptible to zinc deficiency and tissues that require continuous cell replication (skin, immune system) produce the most striking symptoms of zinc deficiency. However, in the case of the brain, where extensive cell replication takes place only during early development, other functions of zinc require more attention (see Table 3). As focus shifts from critical periods and brain growth in malnutrition research, a similar change is appropriate for research on developmental zinc deficiency and behavior.
The role of zinc in brain has received systematic study only within the past 10 y. As described extensively in a review by Frederickson (1989), zinc is important to the function of a number of enzymes and other proteins, including some unique to brain and important to neurotransmission. In addition, zinc functions in membrane stabilization and permeability. Also, as noted earlier, the mossy fiber system of the hippocampus contains vesicular zinc that appears to function in connection with specific neurotransmitters. However, it is not clear at this time what, if any, influence dietary zinc deprivation has on the function of zinc-dependent systems in brain.
TABLE 3
Potential mechanisms of zinc deprivation effects on behavior
|
Roles of zinc in the CNS |
|
• Protein structure |zinc finger) |
|
• Enzyme activity (catalytic site) |
|
• Neurotransmitter action (ligand gated ion channels) |
|
• Hippocampal function (mossy fiber system) |
|
Extra-CNS influences on CNS function |
|
• Neurotransmitter precursor production (liver) |
|
• Hormone/growth factor transport and receptor binding |
|
• Receptor binding (GH, NGF) |
|
• Hormone/toxicant metabolism (liver, testes) |
|
• Energy supply (pancreatic insulin production) |
|
Indirect influences on CNS function |
|
• Adrenocortical activation due to starvation |
|
• Altered tissue trace metal content, especially copper |
|
• Smaller body size due to reduced food intake/growth |
|
• Selective mortality |
It is important to note that there is considerable brain sparing as regards zinc homeostasis. Brain turnover is slow, intracellular zinc concentrations are maintained by an active uptake process and zinc is tightly bound in metalloenzymes and structural proteins (zinc fingers) (Frederickson 1989). In addition, a unique zinc-inducible metallothionein has been found in the brain (Soumillion et al. 1 992,) which presumably plays a homeostatic role. Indeed, only a few dietary zinc deprivation regimens proved effective in reducing brain zinc even for short time periods. Brain zinc was lowered 20 and 37% in 1 5-d-old mouse pups deprived of zinc from d 15 gestation; however, this effect was not seen at 10 or 21 d of age (Golub et al. 1986). Hippocampal zinc staining was reduced in severely growth retarded 18 to 20-d-old rat pups deprived of zinc throughout lactation (Dreosti et al. 1981). Thus, zinc deprivation and zinc deficiency cannot be assumed to be reflected in brain zinc status. This lends emphasis to examination of mediation of behavioral change by non-CNS systems that secondarily impact brain.
Animal studies produce zinc deficiency in isolation from any other nutritional deprivation and under optimal health and environmental conditions. Precise and consistent levels of deprivation for predetermined periods of time are used. This is in contrast to the situation in malnourished children in which multiple deficiencies of varying extent exist for undetermined periods during development. The advantage of animal studies is that direct, causal relationships can be determined, in contrast to human studies, in which inference about causation is limited. Supplement studies in children provide a stronger basis for causal inference; however, they are limited to understanding the causal factors in rehabilitation, not in etiology (Golden 1991). In this sense, animal studies can be seen as providing basic information about how single nutrient deficiency affects behavioral development and how to prevent the adverse effects of deprivation, whereas human studies tell more about how single nutrient deficiencies fit into the constellation of factors determining behavioral well-being of children and how valuable single nutrient supplements are in improving the behavioral well-being of deficient children. Both types of studies are necessary and valuable, but integration of findings must be undertaken with an appreciation for the different aims and designs of these types of research.
The authors thank their colleagues associated with the dietary zinc deprivation project at the California Regional Primate Research Center for continuing support and input.
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