Deletion of the Coffin-Lowry syndrome gene Rsk2 in mice is associated with impaired spatial learning and reduced control of exploratory behavior.

Coffin-Lowry Syndrome (CLS) is an X-linked syndromic form of mental retardation associated with skeletal abnormalities. It is caused by mutations of the Rsk2 gene, which encodes a growth factor regulated kinase. Gene deletion studies in mice have shown an essential role for the Rsk2 gene in osteoblast differentiation and function, establishing a causal link between Rsk2 deficiency and skeletal abnormalities of CLS. Although analyses in mice have revealed prominent expression of Rsk2 in brain structures that are essential for learning and memory, evidence at the behavioral level for an involvement of Rsk2 in cognitive function is still lacking. Here, we have examined Rsk2-deficient mice in two extensive batteries of behavioral tests, which were conducted independently in two laboratories in Zurich (Switzerland) and Orsay (France). Despite the known reduction of bone mass, all parameters of motor function were normal, confirming the suitability of Rsk2-deficient mice for behavioral testing. Rsk2-deficient mice showed a mild impairment of spatial working memory, delayed acquisition of a spatial reference memory task and long-term spatial memory deficits. In contrast, associative and recognition memory, as well as the habituation of exploratory activity were normal. Our studies also revealed mild signs of disinhibition in exploratory activity, as well as a difficulty to adapt to new test environments, which likely contributed to the learning impairments displayed by Rsk2-deficient mice. The observed behavioral changes are in line with observations made in other mouse models of human mental retardation and support a role of Rsk2 in cognitive functions.

Learning impairments and motor dysfunctions in adult Lhx5-deficient mice displaying hippocampal disorganization.

Lhx5 is a member of the LIM homeobox gene family that regulates development of the nervous system. Adult mice generated with a mutation in Lhx5 were found to display absent or disorganized hippocampal neuroanatomy. The pyramidal cell layer in Ammon's horn and the granule cell layer in the dentate gyrus were absent or poorly defined in the hippocampus of adult Lhx5 knockout mice. Behavioral phenotyping of Lhx5 null mutants detected deficits on learning and memory tasks, including the Barnes maze spatial learning task, spontaneous alternation recognition memory, and contextual and cued fear conditioning. General health, neurological reflexes, and sensory abilities appeared to be normal in Lhx5 knockout mice. Motor tests showed impaired performance on some measures of motor activity, coordination, balance, and gait. These results reveal functional outcomes of Lhx5 gene deletion on the integrity of hippocampal neuroanatomy and behavior in the adult mouse.

CA1-specific N-methyl-D-aspartate receptor knockout mice are deficient in solving a nonspatial transverse patterning task.

In both humans and animals, the hippocampus is critical to memory across modalities of information (e.g., spatial and nonspatial memory) and plays a critical role in the organization and flexible expression of memories. Recent studies have advanced our understanding of cellular basis of hippocampal function, showing that N-methyl-d-aspartate (NMDA) receptors in area CA1 are required in both the spatial and nonspatial domains of learning. Here we examined whether CA1 NMDA receptors are specifically required for the acquisition and flexible expression of nonspatial memory. Mice lacking CA1 NMDA receptors were impaired in solving a transverse patterning problem that required the simultaneous acquisition of three overlapping odor discriminations, and their impairment was related to an abnormal strategy by which they failed to adequately sample and compare the critical odor stimuli. By contrast, they performed normally, and used normal stimulus sampling strategies, in the concurrent learning of three nonoverlapping concurrent odor discriminations. These results suggest that CA1 NMDA receptors play a crucial role in the encoding and flexible expression of stimulus relations in nonspatial memory.

Behavioral effects of ivermectin in mice.

BACKGROUND AND PURPOSE: Ivermectin is a common anthelmintic drug, widely used in laboratory rodents for treatment of pinworm and mite infestations. We evaluated the action of ivermectin on sensitive behavioral tasks in mice during treatment for mites within a barrier facility. METHODS: A total of 21 (5 males, 16 females) mice (129/SvEv) were used for measuring body weight, open field locomotor activity, and rotarod motor coordination. For acoustic startle and prepulse inhibition, 20 C57BL/6J and 29 AKR/J mice were studied. For the Morris water task, the same 20 C57BL/6J mice were studied. Ivermectin (0.08% sheep drench) was administered in the drinking water of the home cage for 8 weeks. Control groups received normal tap water in identical bottles. RESULTS: Ivermectin did not affect general health, body weight, motor coordination, swimming behavior, or spatial learning in several inbred strains of mice. However, it induced a small but significant effect on some sensitive behaviors. CONCLUSIONS: A cautious approach to initiating ivermectin treatment in mice should be used for sensitive behavioral experiments.

Selectively enhanced contextual fear conditioning in mice lacking the transcriptional regulator CCAAT/enhancer binding protein delta.

CCAAT/enhancer binding protein delta (C/EBPdelta) is a transcriptional regulator implicated in the hepatic acute phase response and in adipogenic and myeloid cell differentiation. We found that C/EBPdelta is widely expressed in the peripheral and central nervous systems, including neurons of the hippocampal formation, indicating a role in neural functions. To examine the role of C/EBPdelta in vivo, we generated mice with a targeted deletion of the C/EBPdelta gene. This mutation does not interfere with normal embryonic and postnatal development. Performance in a battery of behavioral tests indicates that basic neurological functions are normal. Furthermore, performance in a Morris water maze task suggests that C/EBPdelta mutant mice have normal spatial learning. However, in the contextual and auditory-cue-conditioned fear task, C/EBPdelta null mice displayed significantly more conditioned freezing to the test context than did wild-type controls, but equivalent conditioning to the auditory cue. These data demonstrate a selectively enhanced contextual fear response in mice carrying a targeted genomic mutation and implicate C/EBPdelta in the regulation of a specific type of learning and memory.

Neonatal monoaminergic depletion in mice (Mus musculus) improves performance of a novel odor discrimination task.

This experiment examined behavior and neurochemistry in adult mice (Mus musculus) after neonatal depletion of monoaminergic fibers projecting to the neocortex and hippocampus. Lesions were made on Postnatal Day 1; mice developed to adulthood and were assessed on simple odor discrimination (SOD) and odor delayed nonmatch-to-sample (DNMS) tasks, passive avoidance (PA), and locomotor activity. On SOD, lesioned mice performed faster than controls but with similar accuracy. On the DNMS task, the lesioned mice performed faster and more accurately than controls. On PA, the lesioned mice exhibited a retention deficit relative to controls. Locomotor activity was similar in the 2 groups. Postmortem analyses revealed that the lesions reduced significantly norepinephrine and serotonin levels in both the neocortex and hippocampus. The data suggest that cortically projecting monoaminergic fibers play an important role in normal cognitive development.

Case presentation: Jean.

This symposium was devoted to the consideration of Dr. Mary Libbey's treatment of a 22-year-old woman. The unfolding of the analysand's symbiotic attachment to her mother, the devastating sequelae of her having been the stable center of a pathological family that devoted itself to the care of a severely handicapped sibling, and her immersion in unresolved mourning form the center of this richly detailed and carefully reported case study. In addition, four verbatim sessions are reported, one from each year of the first two years of treatment, and two from the third year of treatment. Dr. Epstein's discussion, praising Dr. Libbey's therapeutic skill, makes note of the issues in the patient's family of origin that served to prepare her to feel endangered in the treatment. Dr. Epstein's view is that the analyst has created an analytic situation that, because it is minimally impinging, allows the patient to become increasingly aware of her unmet needs in a way that is tolerable and minimally "destabilizing to the symbiotically based organization of her internal self and object world." In the climate of safety created in the treatment, the patient can begin to complete the work of mourning for her sister, friend, and aunt, a process of mourning that would be impossible in the context of her nuclear family, centered as it is on a mother who cannot tolerate separation. Limit-setting in the treatment is seen to be reassuring to the patient, facilitating as it does the analyst's commitment to maintaining the integrity of the analytic situation. Dr. Schafer's discussion, while in agreement with Dr. Epstein in recognizing the excellence of the presentation and the sensitivity and hard work that had gone into both the treatment and the clinical presentation, included some specific and focused observations about the transference and countertransference situations prevailing in this treatment and also some suggestions for creating a more consistently safe analytic atmosphere for this particular patient and others like her. Dr. Schafer proposes that the therapist acknowledge to herself and accept as well as possible the inevitable feeling of helplessness such patients provoke. In a more concrete vein, he advocates talking in the first person declarative as much as possible, preferring "I don't understand" to the more standard "What do you mean?" or "Why?" The therapist is encouraged to eschew interpreting what the patient says about the therapeutic relationship for a long time, and, further, he suggests not quickly connecting or easily reducing the therapeutic relationship to childhood prototypes.(ABSTRACT TRUNCATED AT 400 WORDS)

Family orientation: initiating patients and their families to psychiatric hospitalization.

Multiple family groups have been used for some time as a treatment for hospitalized psychiatric patients. However, there is no indication that they have been used in orienting patients and their families during the traumatic intitial period on the inpatient ward. The authors describe the use of family orientation group meetings on the psychiatric inpatient ward of a university hospital. The theoretical bases of the group format are explained and the kinds of information relayed to parents and patients are outlined. The authors believe that use of one-time orientation meetings can help turn the crucial initial period into a therapeutic gain for the patient.

MLA certification: the certification program and education for medical librarianship.

The certification program was formally adopted by the Medical Library Association in 1948 in an attempt to establish standards for medical librarians. The program is reviewed, and some of its effects on education for medical librarians are discussed. At the time of its adoption the program defined the kind of education librarians in the field thought necessary for work in medical libraries. New techniques and a shortage of personnel demand consideration of new educational programs, and the Medical Library Assistance Act will provide the means for their establishment. The Association should assume leadership in determining what and where these programs should be and should evaluate its certification and standards programs as often as current needs require.