Brain Research 887 (2000) 484–487
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Short communication
Avoidance learning in autoimmune mice
a a ,1 a ,2 a a
S.A. Baloght , N.S. Waters
, L.A. Hyde
, C.S. McDowell , C.M. Casler ,
a,b ,
*
V.H. Denenberg
a
University of Connecticut, Biobehavioral Sciences Graduate Degree Program, Storrs, CT, 06269-4154, USA b
University of Connecticut, Department of Psychology, Storrs, CT 06269-4154, USA
Received 27 June 2000; accepted 3 October 2000
Abstract
Previous studies have shown that autoimmune mice perform very poorly on active avoidance learning tasks. In the current studies, mice with lupus-like systemic autoimmunity were able to learn active, as well as passive, avoidance protocols with shock as reinforcement. Therefore, the behavioral deficits seen in active avoidance tasks are not a consequence of the use of electric shock. Rather, the current findings suggest that the inability of autoimmune mice to learn shock motivated responding is due to multiple performance factors, including shock level and properties of the testing apparatus. 2000 Elsevier Science B.V. All rights reserved.
Theme: Neural basis of behavior
Topic: Learning and memory: systems and functions
Keywords: Autoimmunity; Shuttlebox; Passive learning; Lupus; Inbred mice; BXSB; DBA; BW; NZB; Footshock
Despite learning the spatial Morris and radial-arm water [22], suggesting that the aforementioned behavioral im-mazes, as well as non-spatial discrimination learning [1– pairments of autoimmune mice are the result of charac-4,6,8,13,20,22,28], NZB, BXSB, and NZB X NZW F1 teristics of the apparatus and / or parameters used to train (BW) mice, which display severe autoimmunity resem- particular mouse strains, rather than a general cognitive bling systemic lupus-erythematosus [16,27], have been impairment. While previous studies have addressed the reported as being unable to learn to avoid shock, or relationship between avoidance learning and non-cognitive perform poorly in active avoidance protocols, even after variables, such as shock sensitivity and anxiety extensive training [5,8,11,12,14,15,17,20,21,25,29]. In ad- [19,23,24,26], the specific effect of shock level on learning dition, active avoidance learning scores have been shown has not been investigated in autoimmune mouse strains. to be inversely related to degree of autoimmunity [7,9,22]. The current studies, therefore, sought to determine if However, recent studies have found that varying be- autoimmune mice could learn to avoid shock (a) in a havioral contingencies can enhance the acquisition of shuttlebox, in both passive and active avoidance situations, active avoidance in autoimmune mice. For example, and (b) when the level of shock used as motivation was learning was facilitated when cue salience and trial spacing altered.
were increased and when cue contingencies were clarified
Passive avoidance:
The behavioral test consisted of a single training trial, followed 24 h later by a test trial. Gemini Avoidance *Corresponding author. Tel.: 11-860-486-3826; fax: 11-860-486- shuttlebox apparatuses (San Diego Instruments) were used.
3827. A small opening at floor level separated the box into two
E-mail address: [email protected] (V.H. Denenberg). chambers. For the Training trial, each subject was placed 1
Present address: Pharmaceutical Research Associates, Inc., 2400 Old
in the start chamber for a 10 s adaptation period, following Ivy Rd., Charlottesville, VA 22903, USA.
2 which the start chamber was illuminated, and a guillotine
Present address: Department of Pediatrics and Psychiatry, University
of Colorado School of Medicine, Denver, CO 80262, USA. door opened exposing a dark chamber. When the subject
S.A. Baloght et al. / Brain Research 887 (2000) 484 –487 485
entered the dark side, the guillotine door closed and the 0.07) at the lower level. Again, the two groups did not subject received a scrambled footshock for 2 s. The subject differ (z521.2). Only among the BWs was there an effect was then removed from the shuttlebox, and the time to of shock level (z522.0, P,0.05); subjects trained at the enter the dark chamber was recorded. The Test trial lower level did not show significant learning (z521.6), occurred 24 h later, and was identical to the Training trial while those trained at 0.4 mA did (z520.29, P,0.01). except that if the subject entered the dark chamber the
guillotine door closed and no shock was delivered. The test Active avoidance learning:
had a maximum duration of 400 s. The subjects were 80 (41 male, 39 female) BXSB mice In Experiment 1, six male BXSB-MpJ-Yaa (autoim- bred at the Developmental Psychobiology Laboratory at mune) and five male DBA / 2J (non-autoimmune) mice the University of Connecticut. Prior to testing, the mice (hereafter BXSB and DBA, respectively) bred in the were split into two groups. The 0.2 mA group consisted of University of Connecticut’s Developmental Psychobiology 60 animals (31 male, 29 female); the 0.4 mA group was Laboratory served as subjects. The mice were singly comprised of 20 animals (10 male, 10 female). The 0.2 mA housed, following weaning, on a 12-h Light / Dark cycle group had received water escape and Morris water maze (lights on at 0600 h) with food and water ad libitum. These testing prior to shuttlebox avoidance conditioning. The 0.4 strains were chosen because of their immunity profiles and mA group received shuttlebox avoidance conditioning their prior involvement in immune work [7]. They received only. The water escape and Morris water maze data will
2.0 mA of shock for 2 s. not be presented.
In Experiment 2, the levels of shock selected, 0.2 and The same Gemini Avoidance system used for passive 0.4 mA, were similar to those previously used for active learning was used here. The animal’s location was sensed avoidance conditioning. The subjects were 21 female via infrared beams located in each compartment. The BXSB, nine female NZB / BINJ (NZB), and 23 male mice conditioned stimulus (CS) was a light, and the CS–US of the F1 cross of NZB and NZW/ LacJ (BW) mice, interval was 5 s. When shock occurred, the CS remained housed as above. Within each strain, subjects were ran- on. If the animal ran into the opposite compartment, both domly assigned to a high (0.4 mA) or low (0.2 mA) shock shock and light went off, and an average 20 (65) s group. intertrial interval (ITI) started. If the mouse did not cross Due to heterogeneity of variance in both experiments, to the other compartment after 20 s of shock, both shock non-parametric statistical tests were performed. Training and light went off and the ITI started. During the ITI the and Test trials were compared using a Wilcoxon Signed- mouse could move freely between compartments.
rank Test, and group comparisons were made using a Each trial was classified as an avoidance (crossing to the Mann–Whitney U-test. Table 1 gives median latencies and other side prior to shock onset), an escape (crossing to the interquartile ranges (IQR). In Experiment 1, among the other side after shock had started), or a null (remaining in BXSBs, but not DBAs, there was a significant effect of the original compartment and receiving 20 s of shock). In training (z522.2, P,0.03 for BXSB; z521.5 for DBA). addition, time to avoid and time to escape, were scored. At However, the difference between the two groups was not the start of each day’s testing, each animal was given a significant on the Testing trial (z521.29). 5-min adaptation period in the apparatus and could move In Experiment 2, BXSB mice showed learning at both freely between compartments. Each mouse received 50 shock levels (z522.9 and 22.8 for 0.2 and 0.4 mA trials per day for 10 days. Mice received shuttlebox respectively; both P’s,0.01), and the two groups did not avoidance conditioning at approximately 11 and 10 weeks differ from each other (z520.6). Among the NZBs, there of age for the 0.2 and 0.4 mA group, respectively. was an effect of training at the higher shock level (z52 Repeated measures ANOVAs were used to evaluate the 2.0, P,0.05), and a near significant effect (z521.8, P, learning data, presented in Table 2, with Sex and Shock Level as the independent variables and Days as the
Table 1 repeated measures factor. The mice in the 0.2 mA group
Median time to enter dark compartment (6IQR) for Experiments 1 and 2
Experiment Strain Shock N Training Test Table 2
(mA) (s) (s) Active avoidance means (6S.E.M.) for each measure in Experiment 3
1 BXSB 2.0 6 11.269.5 363.56103.8* Shock level
DBA 2.0 5 31.3656.6 205.06341.7
0.2 mA 0.4 mA
2 BXSB 0.2 11 27.3619.1 91.66326.1**
Measures (N560) (N520)
0.4 10 20.5624.4 400.06184.4**
NZB 0.2 4 17.9641.5 129.86128.0[ Avoids 14.7861.05 13.8361.82 0.4 5 14.7644.7 154.06224.2* Escapes 31.1760.88 25.2761.53**
a
BW 0.2 12 22.2622.3 37.2642.8 Nulls 4.0460.84 10.9061.46**
a
0.4 11 18.1610.5 77.96117.8** Avoid time (s) 1.8860.82 2.7160.14** Escape time (s) 6.8160.19 8.3160.32** a
Groups with same letter differ from each other, P,0.01.
486 S.A. Baloght et al. / Brain Research 887 (2000) 484 –487
made more escape responses [F( 1,76 )511.22, P,0.01] and Acknowledgements
fewer nulls [F( 1,76 )516.42, P,0.001] when compared to
mice receiving 0.4 mA shock. The 0.2 mA group also took The authors wish to thank Nancy Talgo, for technical less time to make both avoidance and escape responses assistance, and Dr. Lisa Schrott for helpful comments on [F ’s( 1,76 )524.91 and 16.17, P’s,0.001]. The groups did previous drafts of this manuscript. Supported, in part, by not differ in number of avoidance responses. On the first NICHHD grant HD20806.
day of testing the mice averaged approximately 5.5 avoidances, increased to nearly 18 on Day 10, and showed a significant learning curve [Trials F( 9,711 )522.75, P,
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