Modular, Circuit-Based Interventions Rescue Hippocampal-Dependent Social and Spatial Memory in a 22q11.2 Deletion Syndrome Mouse Model.

BACKGROUND: 22q11.2 deletion syndrome (22qDS) manifests with myriad symptoms, including multiple neuropsychiatric disorders. Complications associated with the polygenic haploinsufficiency make 22qDS symptoms particularly difficult to manage with traditional therapeutic approaches. However, the varying mechanistic consequences often culminate to generate inappropriate regulation of neuronal circuit activity. We explored whether managing this aberrant activity in adults could be a therapeutically beneficial strategy. METHODS: To assess and dissect hippocampal circuit function, we performed functional imaging in acute slices and targeted eloquent circuits (specific subcircuits tied to specific behavioral tasks) to provide relevant behavioral outputs. For example, the ventral and dorsal CA1 regions critically support social and spatial discrimination, respectively. We focally introduced chemogenetic constructs in 34 control and 24 22qDS model mice via adeno-associated viral vectors, driven by excitatory neuron-specific promoter elements, to manipulate circuit recruitment in an on-demand fashion. RESULTS: 22qDS model mice exhibited CA1 excitatory ensemble hyperexcitability and concomitant behavioral deficits in both social and spatial memory. Remarkably, acute chemogenetic inhibition of pyramidal cells successfully corrected memory deficits and did so in a regionally specific manner: ventrally targeted constructs rescued only social behavior, while those expressed dorsally selectively affected spatial memory. Additionally, manipulating activity in control mice could recapitulate the memory deficits in a regionally specific manner. CONCLUSIONS: These data suggest that retuning activity dysregulation can rescue function in disease-altered circuits, even in the face of a polygenetic haploinsufficiency with a strong developmental component. Targeting circuit excitability in a focal, modular manner may prove to be an effective therapeutic for treatment-resistant symptoms of mental illness.

Circuit-based interventions in the dentate gyrus rescue epilepsy-associated cognitive dysfunction.

Temporal lobe epilepsy is associated with significant structural pathology in the hippocampus. In the dentate gyrus, the summative effect of these pathologies is massive hyperexcitability in the granule cells, generating both increased seizure susceptibility and cognitive deficits. To date, therapeutic approaches have failed to improve the cognitive symptoms in fully developed, chronic epilepsy. As the dentate's principal signalling population, the granule cells' aggregate excitability has the potential to provide a mechanistically-independent downstream target. We examined whether normalizing epilepsy-associated granule cell hyperexcitability-without correcting the underlying structural circuit disruptions-would constitute an effective therapeutic approach for cognitive dysfunction. In the systemic pilocarpine mouse model of temporal lobe epilepsy, the epileptic dentate gyrus excessively recruits granule cells in behavioural contexts, not just during seizure events, and these mice fail to perform on a dentate-mediated spatial discrimination task. Acutely reducing dorsal granule cell hyperactivity in chronically epileptic mice via either of two distinct inhibitory chemogenetic receptors rescued behavioural performance such that they responded comparably to wild type mice. Furthermore, recreating granule cell hyperexcitability in control mice via excitatory chemogenetic receptors, without altering normal circuit anatomy, recapitulated spatial memory deficits observed in epileptic mice. However, making the granule cells overly quiescent in both epileptic and control mice again disrupted behavioural performance. These bidirectional manipulations reveal that there is a permissive excitability window for granule cells that is necessary to support successful behavioural performance. Chemogenetic effects were specific to the targeted dorsal hippocampus, as hippocampal-independent and ventral hippocampal-dependent behaviours remained unaffected. Fos expression demonstrated that chemogenetics can modulate granule cell recruitment via behaviourally relevant inputs. Rather than driving cell activity deterministically or spontaneously, chemogenetic intervention merely modulates the behaviourally permissive activity window in which the circuit operates. We conclude that restoring appropriate principal cell tuning via circuit-based therapies, irrespective of the mechanisms generating the disease-related hyperactivity, is a promising translational approach.

Improving temporal cognition by enhancing motivation.

Increasing motivation can positively impact cognitive performance. Here we employed a cognitive timing task that allows us to detect changes in cognitive performance that are not influenced by general activity or arousal factors such as the speed or persistence of responding. This approach allowed us to manipulate motivation using three different methods; molecular/genetic, behavioral and pharmacological. Increased striatal D2Rs resulted in deficits in temporal discrimination. Switching off the transgene improved motivation in earlier studies, and here partially rescued the temporal discrimination deficit. To manipulate motivation behaviorally, we altered reward magnitude and found that increasing reward magnitude improved timing in control mice and partially rescued timing in the transgenic mice. Lastly, we manipulated motivation pharmacologically using a functionally selective 5-HT2C receptor ligand, SB242084, which we previously found to increase incentive motivation. SB242084 improved temporal discrimination in both control and transgenic mice. Thus, while there is a general intuitive belief that motivation can affect cognition, we here provide a direct demonstration that enhancing motivation, in a variety of ways, can be an effective strategy for enhancing temporal cognition. Understanding the interaction of motivation and cognition is of clinical significance since many psychiatric disorders are characterized by deficits in both domains.

Correction to Ward et al. (2015).

Reports an error in "The impact of motivation on cognitive performance in an animal model of the negative and cognitive symptoms of schizophrenia" by Ryan D. Ward, Vanessa Winiger, Kerin K. Higa, Julia B. Kahn, Eric R. Kandel, Peter D. Balsam and Eleanor H. Simpson (Behavioral Neuroscience, 2015[Jun], Vol 129[3], 292-299). There is a text error in the 4th paragraph of the Discussion section. The explanation for the abbreviation OFC was incorrectly listed as occipitofrontal circumference. It should have been orbitofrontal cortex. (The following abstract of the original article appeared in record 2015-18639-001.) Interactions between motivation and cognition are implicated in producing functional impairments and poor quality of life in psychiatric patients. This interaction, however, is not well understood at either the behavioral or neural level. We developed a procedure for mice in which a cognitive measure, sustained attention, is modulated by a motivationally relevant signal that predicts reward probability on a trial-by-trial basis. Using this paradigm, we tested the interaction between motivation and cognition in mice that model the increased striatal D2 receptor activity observed in schizophrenia patients (D2R-OE mice). In control mice, attention was modulated by signaled-reward probability. In D2R-OE mice, however, attention was not modulated by reward-related cues. This impairment was not due to any global deficits in attention or maintenance of the trial-specific information in working memory. Turning off the transgene in D2R-OE mice rescued the motivational modulation of attention. These results indicate that deficits in motivation impair the ability to use reward-related cues to recruit attention and that improving motivation improves functional cognitive performance. These results further suggest that addressing motivational impairments in patients is critical to achieving substantive cognitive and functional gains.

The impact of motivation on cognitive performance in an animal model of the negative and cognitive symptoms of schizophrenia.

Interactions between motivation and cognition are implicated in producing functional impairments and poor quality of life in psychiatric patients. This interaction, however, is not well understood at either the behavioral or neural level. We developed a procedure for mice in which a cognitive measure, sustained attention, is modulated by a motivationally relevant signal that predicts reward probability on a trial-by-trial basis. Using this paradigm, we tested the interaction between motivation and cognition in mice that model the increased striatal D2 receptor activity observed in schizophrenia patients (D2R-OE mice). In control mice, attention was modulated by signaled-reward probability. In D2R-OE mice, however, attention was not modulated by reward-related cues. This impairment was not due to any global deficits in attention or maintenance of the trial-specific information in working memory. Turning off the transgene in D2R-OE mice rescued the motivational modulation of attention. These results indicate that deficits in motivation impair the ability to use reward-related cues to recruit attention and that improving motivation improves functional cognitive performance. These results further suggest that addressing motivational impairments in patients is critical to achieving substantive cognitive and functional gains.

Medial prefrontal lesions in mice impair sustained attention but spare maintenance of information in working memory.

Working memory and attention are complex cognitive functions that are disrupted in several neuropsychiatric disorders. Mouse models of such human diseases are commonly subjected to maze-based tests that can neither distinguish between these cognitive functions nor isolate specific aspects of either function. Here, we have adapted a simple visual discrimination task, and by varying only the timing of events within the same task construct, we are able to measure independently the behavioral response to increasing attentional demand and increasing length of time that information must be maintained in working memory. We determined that mPFC lesions in mice impair attention but not working memory maintenance.