Highlights d Cortical connections decrease in a DiGeorge/22q11 deletion syndrome mouse model d Under-connectivity reflects reduced dendrite, axon, and synapse growth d Txrnd2, a 22q11 gene, regulates mitochondrial metabolism and neuron growth d Cortical connections and behavioral deficits are restored by anti-oxidant therapy

To test whether the rhinal cortex (i.e., entorhinal and perirhinal cortex) plays a time-limited role in information storage, eight rhesus monkeys were trained to criterion on two sets of 60 object discrimination problems, one set at each of two different time periods separated by 15 weeks. After the monkeys had learned both sets, two groups balanced for preoperative acquisition rates were formed. One group received bilateral ablation of the rhinal cortex (n ϭ 4), and the other was retained as an unoperated control group (n ϭ 4). After a 2 week rest period, monkeys were assessed for retention of the object discrimination problems. Retention was significantly poorer in monkeys with removals of the rhinal cortex relative to the controls (68 vs 91%). Although both groups showed slightly better retention of problems from the more recently learned set, there was no evidence of a differential effect of the cortical removal across sets (i.e., no temporal gradient). In addition, the monkeys with rhinal cortex lesions subsequently learned three new sets of 10 object discrimination problems as quickly as the controls did, thus ruling out the possibility of a gross impairment in visual perception or discrimination abilities. Furthermore, they retained these postoperatively learned object discriminations as well as the controls did. The findings indicate that the rhinal cortex is critical for the storage and/or retrieval of object discrimination problems that were learned up to 16 weeks before rhinal cortex ablation; however, in the absence of the rhinal cortex, efficient learning and retention of new discrimination problems can still occur. Key words: visual discrimination; stimulus memory; retrograde amnesia; entorhinal cortex; perirhinal cortex; rhesus monkeyBilateral damage to the medial temporal lobe in humans typically results in a temporally graded retrograde amnesia, in which recent memories are lost although remote memories are spared, as well as severe anterograde amnesia, which is characterized by rapid forgetting of new information (e.g., Scoville and Milner, 1957). The phenomenon of temporally graded retrograde amnesia is consistent with the idea of memory consolidation (see McGaugh and Herz, 1972) and with the idea that the role of medial temporal lobe structures is only temporary. Presumably, as time passes after the original learning episode, memories that were initially dependent on these areas are eventually consolidated into a more permanent state elsewhere (for review, see Squire and Alvarez, 1995).Z ola-Morgan and Squire (1990) found that monkeys with damage to the hippocampal formation, entorhinal cortex, and parahippocampal cortex exhibited temporally graded retrograde amnesia, and they concluded that the hippocampal formation has a time-limited role in memory. Furthermore, similar findings have now been reported in rats (Winocur, 1990;K im and Fanselow, 1992; cf. Bolhuis et al., 1994;Cho et al., 1995) and rabbits (Kim et al., 1995) after lesions of the hippocampal formation. Thus, it seems that the ...

Understanding the developmental etiology of autistic spectrum disorders, attention deficit/hyperactivity disorder and schizophrenia remains a major challenge for establishing new diagnostic and therapeutic approaches to these common, difficult-to-treat diseases that compromise neural circuits in the cerebral cortex. One aspect of this challenge is the breadth and overlap of ASD, ADHD, and SCZ deficits; another is the complexity of mutations associated with each, and a third is the difficulty of analyzing disrupted development in at-risk or affected human fetuses. The identification of distinct genetic syndromes that include behavioral deficits similar to those in ASD, ADHC and SCZ provides a critical starting point for meeting this challenge. We summarize clinical and behavioral impairments in children and adults with one such genetic syndrome, the 22q11.2 Deletion Syndrome, routinely called 22q11DS, caused by micro-deletions of between 1.5 and 3.0 MB on human chromosome 22. Among many syndromic features, including cardiovascular and craniofacial anomalies, 22q11DS patients have a high incidence of brain structural, functional, and behavioral deficits that reflect cerebral cortical dysfunction and fall within the spectrum that defines ASD, ADHD, and SCZ. We show that developmental pathogenesis underlying this apparent genetic “model” syndrome in patients can be defined and analyzed mechanistically using genomically accurate mouse models of the deletion that causes 22q11DS. We conclude that “modeling a model”, in this case 22q11DS as a model for idiopathic ASD, ADHD and SCZ, as well as other behavioral disorders like anxiety frequently seen in 22q11DS patients, in genetically engineered mice provides a foundation for understanding the causes and improving diagnosis and therapy for these disorders of cortical circuit development.

An automated method is described for the behavioral testing of mice in an apparatus that allows computer-graphic stimulus material to be presented. Mice responded to these stimuli by making a nose-poke toward a computer monitor that was equipped with a touchscreen attachment for detecting responses. It was found that C57BL/6 mice were able to solve single-pair visual discriminations as well as 3-pair concurrent visual discriminations. The finding that mice are capable of complex visual discriminations introduces the possibility of testing mice on nonspatial tasks that are similar to those used with rats, monkeys, and humans. Furthermore, the method seems particularly well suited to the comprehensive behavioral assessment of transgenic and gene-knockout models.

A visual discrimination protocol similar to that used with monkeys was adapted to measure attentional set-shifting in mice. An automated touchscreen procedure with compound visual stimuli was used to train mice to attend to 1 of 2 stimulus dimensions (lines or shapes). On a 2nd problem with new stimuli, the mice were required to attend to the same dimension (intradimensional [ID] shift) or switch to the previously irrelevant dimension (extradimensional [ED] shift). Mice readily learned the initial compound discrimination and following shift problem, but there was no ID-ED difference. The fact that mice can be tested with stimuli and task sequences similar to those used with primates suggests that this method can be used to directly compare higher cognitive functions in diverse species.