Alterations in the Maternal Behavior of Rats Rearing Hypothyroid and Hyperthyroid Offspring

INGRID B. JOHANSON Biopsychology Program

Hunter College o f the City University o f New Yovk New Yovk. New Yovk

To determine whether maternal behavior could serve as a mediator for thyroid hormone effects on behavior, I assessed nesting, nursing, grooming, contact, and retrieval in mothers of hypothyroid, hyperthyroid, and control litters, as well as in mothers of litters receiving thyroxine replacement therapy. Females assigned to the hypothyroid and replacement therapy treatments were placed on a goitrogenic diet of .2% propylthiouracil from Day 15 of gestation to Day 22 postpartum. Hyper- thyroid and replacement therapy pups were injected daily with thyroxine starting on the day of birth. The decline in nesting and nursing was delayed in hypothyroid litters whereas the decline in nesting was accelerated in hyperthyroid litters. Retrieval was not affected, bu t grooming of pups occurred less frequently in hypothyroid and replacement therapy litters. Maternal care received by hypothyroid pups was considered adequate. Maternal behavior may alleviate some of the effects of perinatal hypothyroidism, but does not seem to be responsible for the more severe effects of hypo- thyroidism.

Myriad effects of early hypo- and hyperthyroidism are seen at all levels of organiza- tion: biochemical (Balizs, Cocks, Eayrs, & Kovhcs, 1971); morphological (Eayrs, 1955; Nicholson & Altman, 1972); neurophysiological (Bradley, Eayrs, & Schmalbach, 1960; Salas & Schapiro, 1970); and behavioral (Davenport, 1970; Davenport, Hagquist, & Hennies, 1975; Eayrs, 1964; Schapiro, Salas, & Vukovich, 1970). The question may now be asked whether the effects of thyroid hormone insufficiency or excess are direct or whether they are mediated indirectly. One factor which may be important in mediating effects of early hormone manipulation is the quality of the maternal care shown by the mothers of hypo- and hyperthyroid animals. Such effects are particularly likely in that the behavior shown by a mother has been shown to have marked effects on the behavior of her offspring (Denenberg, Ottinger, & Stephens, 1962).

The common method of inducing perinatal hypothyroidism by giving the pregnant or lactating female a diet including an antithyroid drug may have the effect of inducing

Correspondence should be sent to Dr. Ingrid B. Johanson, North Carolina Division of Mental Health, Research Section, Anderson Hall, Dorothea Dix Hosp., Raleigh, North Carolina 2761 1, U.S.A.

Received for publication 14 April 1978 Revised for publication 1 5 November 1978 Developmental Psychobiology, 13(2): 11 1-121 (1980) 0 1980 by John Wiley & Sons, Inc. 0012-1630/80/00l3-0111$01 .OO

112 JOHANSON

some degree of hypothyroidism within the mother herself. Although hypothyroidism in- duced in adult animals has none of the severe effects seen in neonatal hypothyroidism, the possibility remains that maternal hormone insufficiency affects the maternal behavior of these females. Nursing and nesting are particularly likely to be affected by maternal hypothyroidism. Mixner and Turner (1942) and Crosvenor and Turner (1959) have re- ported that the mother’s level of thyroid hormone affects mammary development and lactation; Richter (1941) has demonstrated that nest building in both male and female rats is increased by thyroidectomy.

Maternal behavior can also be affected by stimuli emanating from the young. Nicoll and Meites (1959) found that lactation could be maintained for over 2 months in rats by periodically replacing litters with young pups. Rosenblatt (1967) has suggested that the changing stimulus properties of normal young are important in the decline of retrieval behavior during the postpartum period. In early hypo- and hyperthyroidism, not only is the behavioral maturity of the infant rat affected; so is the physical maturity of the animal: the young hypothyroid pup appears relatively immature (Scow & Simpson, 1945) and hyperthyroid pups appear more mature than controls (Khamsi & Eayrs, 1966). Thus, one might expect that mothers of hypothyroid pups, being exposed to comparatively immature pups for a longer period of time, would show a delay in the decline of maternal behavior. Similarly, mothers of hyperthyroid pups should show an accelerated decline in maternal responsiveness, in that their young appear to be both behaviorally and physically mature relative to controls. The differences in maternal behavior may then contribute to later differences in the behavior of hypothyroid and hyperthyroid animals.

The maternal behavior of mothers of hypo- and hyperthyroid animals has never been examined, however, I attempted to remedy this in the present investigation.

Method

Subjects

Charles River CD strain rats (Rattus norvegicus) were used throughout the investiga- tion. They were received in the laboratory between the 12th and 15th day of pregnancy (timed by the supplier). Their litters served as subjects in an analysis of the development of home orientation which was studied concurrently with maternal behavior.

Beginning 3 days prior to the expected day of parturition (Day l ) , cages were checked daily at 1000 hours for the presence of new litters. All new litters were con- sidered Day 1 pups. Litter size was reduced to 6 to minimize differences in maternal care received by litters of different sizes and to reduce competition for nipples. An effort was made to maintain an equal number of males and females. Pups which were considerably smaller than the litter average or which had poor color were eliminated.

If a female gave birth to a litter with fewer than 6 pups, same-age foster pups from litters receiving the same prenatal treatment were used to increase the litter size. Foster pups were introduced only on Day 1 and after this day no replacements were made. Data from litters in which fewer than 3 pups survived to Day 22 were discarded (see Table 1).

REARING OF HYPO- AND HYPERTHYROID PUPS 113

TABLE 1. Number of Litters and Pups Used in Each Treatment.

Number of Number of Number of Number of Percentage litters at litters with pups a t pups surviv- of the pups Number start of > 3 pupsat start of ing to surviving of pups

Treatment experiment Day 22 experimenta Day 22 to Day 22 observed b

Hypo thyroid 10 7 56 31 55.4 27

Hyperthyroid 8 8 48 42 87.5 42

Replacem en t therapy 10 9 57c 45 78.9 43

Control 8 8 47d 46 97.8 44

aIncludes pups in litters of less than 3 pups a t Day 22. bExcludes pups in litters of less than 3 pups at Day 22 and foster pups. 'Includes 1 foster pup in each of 2 litters. dIncludes 2 foster pups in 1 litter.

Maintenance

All of the subjects were housed in 32.8 X 37.8 X 16.8-cm polycarbonate cages located in a small animal room. The ambient temperature ranged between 21.1 and 26.7"C, but for the most part remained between 22.2 and 23.3"C. Room lights were on from 0700 to 1900 hours, and all testing was conducted between 0800 and 1800 hours. Food and water were present ad lib.

Design

Four treatment groups were observed in the present investigation. In Group 1 , the hypothyroid treatment group, the mothers received a diet of .2% propylthiouracil (PTU) mixed with powdered Teklad Rat and Mouse Diet (4% fat, 24% protein), starting on Day 15 of pregnancy and the offspring were injected with saline starting at birth. In Group 2, the hyperthyroid treatment group, the mothers were maintained on the Teklad diet with- out PTU and the pups received excess thyroxine starting at birth. In Group 3 , the replace- ment therapy treatment group, the mothers received PTU and the pups received thyroxine starting at birth. In Group 4, the control treatment group, the mothers were maintained on Teklad diet and the pups were injected with saline.

The rationale for including the replacement therapy treatment group in the present study was as follows. In the hypothyroid treatment group, the mother's level of thyroid hormones may have been reduced because PTU was first given to the pregnant or lactating female. If the mothers in this treatment group differed from controls, the difference couid be a result of either maternal or infant hypothyroidism. By including a treatment group in which the mothers were hypothroid but the pups were given replace-

114 JOHANSON

ment therapy, we could determine whether the maternal hypothyroidism or the pup hypothyroidism was responsible for differences in maternal behavior in mothers rearing hypothyroid offspring.

Procedure

Starting on Day 15 of pregnancy, females assigned to the hypothyroid or replace- ment therapy treatments were placed on a goitrogenic diet of .2% propylthiouracil (6-N- propyl-2-thiouraci1, JCN Nutritional Biochemicals, Cleveland, Ohio) mixed with powdered Teklad Rat and Mouse Diet.

Thyroxine solution was prepared by dissolving 2 mg thyroxine (L-thyroxine sodium, Smith Kline & French Laboratories, Philadelphia, Penn.) in 26 m l .01N NaOH and 74 m l .9% NaCl solution. Beginning on Day I , pups assigned to the hyperthyroid treatment were injected daily as follows: Days 1-7, 1 pg thyroxine; Days 8-14, 2 pg thyroxine; and Days 15-22, 4 pg thyroxine. Pups receiving replacement therapy were injected daily as follows: Days 1-7, .8 pg thyroxine; Days 8-14, 1.6 pg thyroxine; and Days 15-22, 3.2 pg thyroxine. The hormone was injected in .05 to .2 ml of fluid. Control and hypothy- roid pups were injected with equivalent amounts of saline.

Pups were numbered from 1 to 6 on their dorsal surface with a nontoxic waterproof black marker. After Day 14, pups were also marked on the tail because markings on the fur become unreliable after this age. Pups were weighed to the nearest .1 g on Day 1 and then every other day between Days 2 and 22. Pups were also examined daily for the presence of complete bilateral eye opening.

Data were collected in 6 replications. In any replication, at least I litter was assigned to each of the 4 treatments.

The following maternal behaviors were assessed: (1) nesting; (2) nursing, grooming of pups by mother, and contact; and (3) retrieval of pups.

Nest Rating

Approximately 18-20 hr before each nest was rated, the existing nest was completely destroyed and the shavings were scattered uniformly on the cage floor. The nest was rated at the same time each day for a given female. Nests were rated daily between Days 2 and 22, using a scale devised by Seitz (1958):

0-no nest, 1-shavings trampled down in one corner of the cage, 2-shavings pushed aside to make a bare spot in the corner of the cage, 3-low ring of shavings around a bare spot in the corner, 4-all shavings in the cage were piled into a high ring around a bare spot in the corner.

Nursing, Grooming, and Contact Two 15-min observations were carried out daily starting on Day 2 and repeated every

other day until Day 22. The 1st 15-min observation was made before disturbing the female and litter and the 2nd observation was made approximately 1 hr after the female and pups were reunited following the retrieval test, and after the weighing, marking and injecting of the pups. The observations of any given litter occurred at the same time each

REARING OF HYPO- AND HYPERTHYROID PUPS 1 15

day, whereas the observations of all litters within a treatment group were randomly dis- tributed through the day.

The 15- min observation period was divided into sixty 15-sec intervals and the follow- ing were noted on a checklist during each interval:

1. Nursing. Mother was considered to be nursing if she was crouched over the pups in the nest area or if at least 2 pups were suckling either beneath or alongside her, and she was not eating, drinking, nest-building, or grooming herself.

2. Grooming of pups. The mother was observed licking 1 or more pups. 3. Contact. Mother was considered in contact with the pups if at least 1 pup was in

direct contact with her body, excluding the tail; the number of pups not in contact with the mother at the end of each 15-sec interval was also noted.

Retrieval

Females were given retrieval tests starting on Day 2 and continuing every other day until Day 14. Retrieval tests were performed immediately after the 1st 15-min observa- tion. The home cages were modified to have a 9.Ocm-wide door which could be raised to allow the female access to the apparatus used in retrieval testing. The door was situated in the center of one of the 32.8-cm walls.

A Plexiglas retrieval alley, which attached to the home cage, was used for retrieval testing. The alley, which measured 33 X 72 X 2 6 c m high, was divided into 2 sections by an opaque partition which could be raised about 10 cm to permit access to the entire alley. One section of the alley held the pups during retrieval testing and the other section served as a holding chamber for the female prior to testing. The floor of the retrieval alley, as well as the opaque partition, was covered with black matte finish contact paper.

The retrieval alley was attached to the home cage and the home cage door was then raised, allowing the mother to move into the holding section. If she did not enter within 2 min, she was picked up and placed in the holding section. After the mother had entered the alley, the home cage door was lowered and the pups were removed to the far end of the retrieval alley. After 2 min, the female was allowed access to the home cage and after an additional 2 min the opaque partition was raised so that the pups were available for retrieval. The latency to contact the first pup, as well as the latency to retrieve each pup into the home cage, was noted. Testing was terminated when all pups were retrieved, or after 5 min had passed.

Results

Differences in the number of pups born to females belonging to the hypothyroid, hyperthyroid, control, or replacement therapy treatment groups were not significant (F < 1 , df = 3/32). However, differences in pup mortality during the litter period were marked: control litters had a survivorship through Day 22 of 97.8%; hyperthyroid litters had a rate of 87.5%; and litters receiving replacement therapy had a survivorship of 78.9%. In contrast, hypothyroid litters had a survivorship through Day 22 of only 55.4%, with none of the pups surviving to maturity. The differences among treatments in mean per- centage surviving in a litter were significant (F = 4.74, d f = 3 /32 ,p < .02).

I16 JOHANSON

Pup Weight

The birth weights of litters whose mothers had received PTU from Day 15 of gesta- tion, that is, the hypothyroid litters and litters receiving replacement therapy, averaged 5.7 g (S.E.M: f .2) and 5.7 g (f .3), respectively, whereas litters not treated prenatally, that is, control and hyperthyroid litters, had mean birth weights of 6.5 g (+ . l ) and 6.7 g (k .3), respectively. These differences in birth weight among the treatment groups were significant (F = 4.99, d f = 3/28, p < .001). Post hoc comparisons revealed that the birth weights of the replacement therapy and hypothyroid pups differed significantly from the birth weights of control and hyperthyroid pups (Fisher t d ; p < .05).

The weight differences among treatments became pronounced as pups grew older; this Age X Treatment interaction was significant (F = 26.67, df= 33/308,p < .001). The hyperthyroid pups did not differ significantly from control pups at any age. Hypothyroid litters differed significantly from control and hyperthyroid pups on Days 14-22 and differed from replacement therapy pups on Days 20 and 22 (Fisher 1sd;p < .05). By Day 22, animals receiving replacement therapy were approximately 26% lighter than controls, whereas hypothyroid pups were 5 1% lighter. The Age effect was significant (F = 1076.77, df = 11/308, p < .OOl), as was the Treatment effect (F = 25.35, df = 3/28, p < ,001).

Eye Opening

Pup hormonal state had a considerable effect on the day of bilateral eye opening (see Fig. 1). Control pups showed the highest frequency of eye opening on Day 15, hyperthy- roid pups on Day 13, hypothyroid pups on Day 18, and pups receiving replacement therapy on Day 14. The groups differed significantly (F = 68.6, df = 3/28, p < .001).

d 16 17 18 19 20 21 22

AGE OF PUPS (days)

Fig. 1. Cumulative percentage of subjects showing complete bilateral eye opening a s a function of age. 0, Hypothyroid (n = 27). A, Replacement therapy ( N = 43). *, Hyperthyroid ( N = 42). A, Con- trol (N = 44).

REARING OF HYPO- AND HYPERTHYROID PUPS 1 17

4.0

3.5

3.0

2.5 u z + 2 2.0

c v) W

1.5 2 <

1.0

0.5

Nest Rating

Early in the litter period, the 4 treatments did not differ in the mean nest rating, with females in all groups maintaining highquality nests; after the 1 st 2 weeks, however. the groups differed significantly (see Fig. 2). The variance analysis revealed a significant effect of Age(F= 59.21,df= 20/560,p < .001), a significant Treatment effect ( F = 20.0, df= 3/28, p < .OOl), and a significant Age X Treatment interaction ( F = 2.37, df= 60/560, p < .OOl). The nests of hypothyroid litters were maintained in better condition for a longer period of time than nests of other litters. From Days 13 to 22, nest ratings from hypothyroid litters were significantly higher than ratings from hyperthyroid litters. Hypothyroid litters differed significantly from controls on Days 14 and 15 and differed from replacement therapy litters on Days 21 and 22 (Fisher lsd; p < .05). The nests of hyperthyroid litters were lower in quality than the nests of control litters on Days 20 ,21 , and 22 (Fisher Isd;p < .05).

Nursing, Grooming, and Contact No marked difference was evident in the data obtained from the 2 daily 15-rnin

observations. For this reason, the results reported for the mother-young interactions (nursing, grooming, and contact) are based on an average of the 2 observations.

Nursing. Nursing behavior appeared to be affected by hormonal treatment. Although the percentages of intervals in which the female was observed in the nursing position were not different among the mothers of control, hyperthyroid, and replacement therapy litters, the mothers of hypothyroid litters were observed to be in the nursing position more often than mothers of other pups (see Fig. 3). A variance analysis indicated signifi-

1 2 4 6 14 16 1% 20 22

A& OF*&PS &ys)

Fig. 2. Mean nest rating as a function of pup age. 0, Hypothyroid ( N = 7). A, Replacement therapy (A'= 9). 0 , Hyperthyroid ( N = 8). A, Control ( N = 8).

118 JOHANSON

cant Age (F = 23.51, df = 10/280, p < .OOl) and Treatment (F = 6.56, df = 3/28, p < .002) effects, and a significant Age X Treatment interaction (F = 1.7, df= 30/280, p < .02). Post hoc comparisons revealed that hypothyroid litters showed higher levels of nursing than hyperthyroid litters on Days 14 and 18, higher levels than control litters on Day 16, and higher levels than litters receiving replacement therapy on Day 14 (Fisher 1sd;p < .05).

Grooming. An analysis of the frequency of maternal grooming of pups led to an un- expected finding. Mothers of hypothyroid and replacement therapy pups maintained a fairly constant, low level of grooming throughout the litter period and did not differ from each other. In contrast, mothers of hyperthyroid and control pups showed a peak in grooming behavior at 10-12 days for controls and at 6-10 days for hyperthyroid litters. A variance analysis of the data indicated no significant Treatment effect (F = 1.59, df = 3 /28 , p > .05), but a significant Age effect (F = 6.27, df = 10/280, p < . O O l ) and a significant Age X Treatment interaction ( F = 2 .08 ,d f z 30/280,p < .001). Mothers in the hypothyroid treatment group differed significantly from mothers in the hyperthyroid group on Day 6 and differed from control mothers on Day 10, whereas mothers of litters receiving replacement therapy differed significantly from mothers of hyperthyroid litters on Days6 and 10 and from control mothers on Day 10 (Fisher 1sd;p < .05). Differ- ences between mothers of hypothyroid pups and mothers of pups receiving replacement therapy were not significant (Fisher 1sd;p > .05).

Contact. Small but significant differences were evident in the mean number of intervals in which mother-young contact occurred among the 4 treatment groups. A variance analysis revealed a significant Treatment (F = 3.16, df = 3/28, p < .05) and a significant Age effect (F = 8.09, df = l0/280, p < .001), as well as a significant Age X

I 2 4 6 0 I 0 12 14 16 I8 a0 22

AGE OF PUPS (days)

big. 3 . Mean percentage of intervals during which nursing occurred in hypothyroid, hyperthy- roid, control, and replacement therapy litters, as a function of age. 0, Hypothyroid (N = 7 ) . A, Replace- ment therapy ( N = 9). ., Hyperthyroid ( N = 8). A, Control ( N = 8).

REARING OF HYPO- AND HYPERTHYROID PUPS 119

Treatment interaction (F = 1.69, df = 30/280, p < .02). Mother-young contact was significantly lower compared to controls on Day 18 for the hyperthyroid treatment group and on Day 22 for the replacement therapy treatment group (Fisher 1sd;p < .05).

Differences also appeared among the 4 groups in the mean percentage of pups not in contact with the female at the end of a 15-min interval. For litters in the 4 treatment groups, the percentage of pups not in contact with the female increased during the pre- weaning period and this Age effect was significant ( F = 18.74, df= 10/280, p < .001). In addition, a significant Treatment effect (F = 4.25, df = 3/28, p < .02) and a significant Age X Treatment interaction (F = 1.53, df = 301280, p < .05) were evident. Compared to replacement therapy and hyperthyroid rat pups, a larger percentage of hypothyroid pups remained in contact with the female and these differences were significant on Day 14 for replacement therapy pups and Day 18 for hyperthyroid pups (Fisher Isd;p < .05).

Retrieval

Contact Latency. The mothers of litters receiving replacement therapy showed longer latencies to contact the 1st pup on Days 2 , 4 , and 6 than did mothers of other pups (see Fig. 4). After this time, the mothers in the 4 treatment groups did not differ. In a variance analysis a significant Age effect was found (F = 5.86, df = 5/140, p < .001). The Treat- ment effect was not significant (F < 1, df = 3/28), but the Age X Treatment interaction was significant (F = 2.04, df= 15/140, p < .02). When the latency data were computed to include only those females that did contact the pups, very few differences remained in the latency to contact pups among mothers of control, hyperthyroid, and hypothyroid litters, whereas mothers of replacement therapy litters showed long contact latencies on Days 6 and 8.

I 2 10 12

&E OF P6PS Cd&

Fig. 4. Mean latency to contact the first pup during the retrieval test, as a function of pup age. A maximum latency of 300 sec was assigned to females that did not contact a pup during the 5-min test. 0, Hypothyroid (N = 7). A, Replacement therapy (N = 9). 0 , Hyperthyroid ( N = 8). A, Control (N = 8).

120 JOHANSON

Retrieval Latency

No differences were evident among the 4 treatment groups in the latency to retrieve the 1 st pup (F = 1.77, df = 3/28, p > .05), although a significant Age effect was found (F = 3.49, df = 5/140, p < .01). No effect of a Treatment X Age interaction was seen (F= .77,df= 15/140,p> .05).

Discussion

The mothers assigned to the 4 treatment groups showed substantial differences in the various measures of maternal behavior. The nests in hypothyroid litters were maintained in better condition for a greater part of the preweaning period than in control litters, whereas in hyperthyroid litters an accelerated decline in nest quality appeared. Pup hormonal condition seemed to have a significant effect on the quality of the nest. Hyper- thyroid litters showed a more rapid decline in nesting than controls, although maternal hormonal state was identical. Likewise, mothers of hypothyroid pups maintained high quality nests longer than mothers of replacement therapy pups, although mothers of both types of litters received PTU. Considerable differences were also found in the amount of nursing, grooming, and mother-young contact. Although the females showed no differ- ences in the amount of nursing shown in the 1st 10 days postpartum, after Day 10 mothers of hypothyroid litters showed higher levels of nursing. After the 1st 7-10 days, the mothers and pups in the hypothyroid and control treatment groups also showed a greater amount of mother-young contact than mothers and pups assigned to the replace- ment therapy and hyperthyroid treatments. Mothers of replacement therapy and hypo- thyroid litters showed low, constant levels of grooming throughout the litter period, whereas the mothers of control and hyperthyroid animals showed large peaks in the amount of grooming between Days 6 and 12. Only small differences in maternal retrieval of pups were found among the 4 treatment groups. The mothers of litters receiving replacement therapy showed longer latencies to contact their pups on the first few days of testing, but because no significant differences appeared in retrieval latencies, the differ- ences in contact latency seem not to be significant for the occurrence of normal retrieval behavior.

In general, the hypothyroid pups appeared to have received adequate maternal care. The higher quality nests found in the hypothyroid treatment group, as well as the in- creased nursing and general contact, might have compensated for the deficiency in thermoregulation found in these pups and may have provided increased nursing oppor- tunities. Moreover, the higher levels of maternal care received by hypothyroid animals may have been responsible for some of the differences in behavior shown by these pups. The development of homing is considerably delayed in hypothyroid rat pups (Johanson, Turkewitz, & Hamburgh, in press); the maintenance of the nest in good condition may make less likely the pups’ departure from the nest, thus preventing the development of homing at the normal time.

The mothers of hyperthyroid pups generally showed a more rapid decline in nest quality and mother-young contact than controls; the accelerated development of the pup may have been responsible for the early decline in maternal behavior. Further, these differences in maternal care could interact with the initial differences shown by hyperthy- roid pups to give rise to altered pup behavior at later ages.

REARING OF HYPO- AND HYPERTHYROID PUPS 121

These data suggest that the severe effects of thyroid hormone manipulation are not mediated via differences in the quality of maternal care received. In fact, the maternal behavior shown by mothers of hypothyroid pups may have alleviated some of the severe deficits produced by perinatal hypothyroidism. However, given the finding that thyroid manipulation of the young does alter maternal behavior, further study of the role of maternal behavior in the development of hypothyroid and hyperthyroid animals would have to be made to determine the extent to which maternal factors are important.

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