Mice that model the 22q11 deletion syndrome were genetically engineered and displayed PPI impairments . Because redoxdysregulation and allelic variants of the genes coding for the rate-limiting glutathione synthesizing enzyme glutamate-cysteineligase modifier have also been implicated in BD, mice with this GCLM knocked out were tested and exhibited PPI deficits . In a genome-wide association study, a relationship between the NCAN gene and BD was observed. Ncan KO mice were subsequently tested and displayed decreased PPI levels, together with a range of other mania-like behaviors , which were normalized after lithium treatment . In another recent study, treatment with valproate reversed PPI deficits observed in transgenic mice over expressing corticotropin-releasing factor, which is implicated in the etiology of BD . Finally, PPI deficits observed in BD have been recapitulated in other animal models that exhibit mania-like behavior such as the Na+, K+-ATPase α3 mutant mice or ClockΔ19 mutant mice , but not in other animal models such as the N-ethyl-N-nitrosourea -generated mutant mouse strain . Furthermore, Black Swiss mice have often been reported as a model for mania yet they exhibited better PPI compared to C57BL/6 mice . Given the observed PPI deficits across numerous disorders, investigating the exploratory and/or other relevant behaviors of these genetic mutants will prove useful for BD research in the future. As previously mentioned, DAT KO mice have also been suggested as a model for mania and their sensorimotor gating capacities have also been assessed. Significant PPI deficits were observed in these mice,commercial vertical farming systems which were attenuated by pretreatment with the DA D2 antagonist raclopride and the antipsychotics clozapine and quetiapine .
DAT KD mice, that have approximately 10% expression of the DAT gene compared to WT mice, initially appeared to have normal PPI levels . More recently however, we have observed PPI deficits in these DAT KD mice . Interestingly, the COMT Val allele, which contributes to slower DA clearance in the prefrontal cortex, is associated with reduced PPI in Caucasian healthy humans . Therefore, a link between reduced DA clearance and PPI deficits has been established. Together, these pharmacological and genetic studies can be helpful in the screening of valid animal models for BD and development of novel therapeutics , although the PPI paradigm by itself is not selective for assessing BD mania treatment efficacy. Furthermore, it is clear that the circuitry underlying PPI is diverse and complex , yet it is unclear whether deficits in models described here are a result of alterations in different circuitry, or whether they exert an effect that converges on one particular circuit. Comparing these manipulations for this convergence would be useful in order to establish whether novel treatments could be elucidated from this work. Importantly, the strength of high-quality translational research is the capacity to assess a battery of different behaviors relevant to the disorder across species .In the case of PPI and BD, mixed results are observed across both models and patients.Neurocognitive capabilities closely correlate with a patients’ functional outcome . Developing treatments targeted at the neurocognitive deficits of patients should therefore enhance their quality of life. Impaired cognition as a quantifiable symptom of BD should be included in the multivariate assessment of screening animal models for BD. Working memory, vigilance, inhibitory control, decision-making under risk, and processing speed can all be affected in BD patients . Some of the cognitive deficits that can be quantified in both humans and rodents include impaired attentional performance, disinhibition, and impaired risk-based decision-making , but further studies in other cognitive domains are required. Translational paradigms assessing such behavior in a similar fashion across species can help bridge the gap between cognitive difficulties in BD and their assessment in animal models for BD.Decision-making performance in a clinical setting is most often measured using a task called the Iowa gambling task .
The IGT is based on repeatedly making choices between four different card decks in order to maximize gains in the long-term . Unknown to the test subject, two options will deliver high monetary gains but with occasionally large losses , while the other two options pay smaller amounts of money but also incur smaller penalties . Initially, healthy individuals will sample all decks but as the task progresses they preferentially choose the advantageous options significantly more as they deliver the highest gains in the long-term. Patients with BD however, choose more disadvantageous or risky choices and learn slower . Hence, BD patients make poorer decisions under risk in a laboratory-based task. In order to study biological mechanisms behind decision-making in more detail, several different rodent versions of the IGT have been developed . One procedure uses an operant-based chamber in which the rodent chooses from four different light cues . Each option is associated with a specific reward/punishment schedule similar to the one used in human IGT. One technique uses such an IGT but trains the rodents on the reinforcement schedules over many sessions with decision-making assessed after contingency acquisition. Using this procedure, the effects of pharmacological manipulations of DA, serotonin, and norepinephrine as well as lesions in the orbitofrontal cortex and amygdala on decision-making for learned contingencies could be studied. When this multi-plesessions IGT paradigm was adopted for use in mice, it was discovered that the DAT KD mouse model for BD tended to exhibit an increased risk-preference compared to WT mice after 25 training sessions . Furthermore, secondary measures indicated elevated levels of motivation and motor impulsivity in these mice. Using the same IGT procedure, the effects of selective DAT inhibition was also studied in mice. GBR12909 and modafinil both increased measures of motor impulsivity and motivation significantly, but affected risk-preference only subtly . In contrast, the mixed DAT/NET inhibitor amphetamine induced a more conservative strategy in both mice and rats , resulting in a risk-averse preference without affecting motor impulsivity. Hence, in this between-sessions IGT, amphetamine reduced risk preference in rodents , while selective DAT inhibition only subtly increased risk preference. Importantly however, the human IGT requires subjects to learn to select the advantageous options over a single session. BD patients learn more slowly in this single task. Thus, a similar time-course of this decision-making process in a rodent IGT may more accurately reflect human decision-making. When tested within a single session, it was possible for rats to learn to select the advantageous options over time in a single 60 min session consistent with healthy humans.
This single-session IGT test was successfully adopted for use in mice, resulting in a single-session IGT more analogous to the human IGT . Using this procedure, it was established that both GBR12909- treated and DAT KD mouse models of BD exhibited poor learning of reward contingencies over a single session consistent with what was observed in manic BD patients performing the human IGT. Additionally, DAT inhibition also increased motivation and motor impulsivity in mice consistent with earlier observations . Perhaps most striking was that using post-hoc choice analyses, it was discovered that decision-making deficits of the BD mania patients and both mouse models were driven by increased sensitivity to rewards,horticulture vertical farming specifically a preference to shift to high reward options. Such findings in patients are consistent with previous reports for mania patients and differ by state of BD, with depressed patients being more sensitive to punishment . Combined, these data indicate that selectively reducing DAT functioning induces a behavioral profile that resembles the impaired decision-making and hedonia behaviors observed in BD mania . These data also highlight that species-specific versions of the IGT provide another useful translational tool that can be used to investigate the biological underpinnings of poor risk-based decision-making in patients with BD . Another typical neuropsychological test that is often used to quantify attention and inhibitory deficits – another core aspect of cognitive dysfunction in BD – is the continuous performance test . Different versions of the CPT exist, but all include both target and non-target stimuli with which attentional processes such as vigilance and response inhibition can be quantified. When patients with BD are tested in the CPT, several studies have demonstrated impaired attentional performance and inhibitory processing deficits compared to healthy subjects . Because vigilance deficits present in BD can be measured this way, vigilance may be another potential target to assess across species . Using the same operant chambers as utilized for the rodent IGT, a 5-choice -CPT was developed for mice , and is also being used in rats . Hence, several measures of vigilance and response inhibition processes can successfully be measured with the 5C-CPT in both mice and rats wherein improved performance was observed in healthy mice and rats , and PCP impaired performance in rats . Subsequently, the 5C-CPT was reverse-translated for use in humans with recent reports describing the first translational assessment of vigilance wherein patients with schizophrenia exhibit impaired performance in the 5C-CPT that is also fMRI compatible . Hence, the human task is clinically sensitive while also demonstrating translational predictive validity. In support of the translational predictive validity of the 5C-CPT, both mice and healthy humans displayed impaired attentional functioning after 36 hours of sleep deprivation . Using the mouse 5C-CPT, it was discovered that DAT KD mice exhibited inhibitory deficits and poor vigilance similar to that of patients with BD mania performing the human 5C-CPT . This translational paradigm could therefore prove useful when assessing attention in rodent models for BD and comparing it with that of patients. These studies are also of importance for future BD research given that sleep deprivation can induce mania in BD patients. While some have therefore suggested that sleep deprivation induces mania-like behavior in rodents, e.g., hyperactivity, increased aggression, hypersexuality, and stereotypy , this premise is somewhat flawed since healthy humans are not ‘manic’ as a result of sleep deprivation. Rather, because sleep deprivation can precipitate manic states in patients , sleep deprivation could be combined with genetic susceptibility models related to BD and tested in the 5C-CPT in an attempt to more closely relate to clinical findings.
Since patients with bipolar depression can actually benefit from sleep deprivation , the same procedure may also be used to validate predictive treatment models of BD depression because if in a ‘depressed’ state, mice should recover from sleep deprivation. Thus, the 5CCPT provides an additional instrument to the behavioral tool set with which behaviors relevant to BD can be screened and associations between environmental manipulations and genetic susceptibility for BD can be studied . Selective inhibition of the DAT recreates several behavioral profiles of BD mania . Perhaps most importantly, risk-preference in the mouse IGT correlated modestly with specific exploration in the mouse BPM . In human studies, a relationship was observed between specific exploration in the BPM and poor performance in the frontal-mediated Wisconsin card-sorting test . In other words, the higher the specific exploration, the more likely subjects were to exhibit impaired cognitive functioning. It is therefore feasible that developing treatments that would attenuate the pervasive specific exploration profile of BD patients seen in mania and euthymic phases may also positively affect a number of cognitive functions. To date, no such attenuation has been observed in published studies in which AMPT or VPA was administered to the DAT mice in the mouse BPM . Instead, both treatments increased levels of specific exploration even further, reflective perhaps of a deleterious effect on cognition. AMPT treatment can indeed impair cognitive functioning as was previously assessed by reward processing and probabilistic learning in human patients with MDD and bulimia nervosa . The mood stabilizer VPA, just as lithium, has also been associated with cognitive deficits in healthy subjects and BD patients . These data highlight the difficulty in studying the predictive pharmacological validity of animal models for BD without a ‘gold standard’ treatment that is efficacious for all symptoms and underscore the need to develop novel treatments that benefit cognition in the already negatively affected BD population. The current review has focused on efforts made to determine what neural mechanisms might contribute to abnormal behaviors that are relevant to BD, particularly mania. This review has focused on translational tests of behavior that are sensitive to deficits in BD patients and in which an equivalent task exists in rodents . Significant progress has been made, but a great deal of work is still required in this field. Reduced DAT functioning appears key to recreating many aspects of behavioral abnormalities seen in BD mania patients . This idea stemmed in part from observations that a DAT polymorphism reduces DAT expression and lower DAT levels are observed in drug-free patients with BD, although these genetic observations in humans are inconsistent. Future studies should determine if patients with genetic polymorphisms exhibit reduced DAT levels and abnormal behaviors in these translational paradigms. Furthermore, other aspects of cognitive functioning rarely tested in animal models of BD such as working memory have not been tested in the DAT model animal.