Zackary A. Cope

Modeling neurodevelopmental cognitive deficits in tasks with cross-species translational validity.

Numerous psychiatric disorders whose cognitive dysfunction links to functional outcome have neurodevelopmental origins including schizophrenia, autism and bipolar disorder. Treatments are needed for these cognitive deficits, which require development using animal models. Models of neurodevelopmental disorders are as varied and diverse as the disorders themselves, recreating some but not all aspects of the disorder. This variety may in part underlie why purported procognitive treatments translated from these models have failed to restore functioning in the targeted patient populations. Further complications arise from environmental factors used in these models that can contribute to numerous disorders, perhaps only impacting specific domains, while diagnostic boundaries define individual disorders, limiting translational efficacy. The Research Domain Criteria project seeks to ‘develop new ways to classify mental disorders based on behavioral dimensions and neurobiological measures’ in hopes of facilitating translational research by remaining agnostic toward diagnostic borders derived from clinical presentation in humans. Models could therefore recreate biosignatures of cognitive dysfunction irrespective of disease state. This review highlights work within the field of neurodevelopmental models of psychiatric disorders tested in cross‐species translational cognitive paradigms that directly inform this newly developing research strategy. By expounding on this approach, the hopes are that a fuller understanding of each model may be attainable in terms of the cognitive profile elicited by each manipulation. Hence, conclusions may begin to be drawn on the nature of cognitive neuropathology on neurodevelopmental and other disorders, increasing the chances of procognitive treatment development for individuals affected in specific cognitive domains.

Schizophrenia and Substance Abuse Comorbidity: Nicotine Addiction and the Neonatal Quinpirole Model

This review focuses on nicotine comorbidity in schizophrenia, and the insight into this problem provided by rodent models of schizophrenia. A particular focus is on age differences in the response to nicotine, and how this relates to the development of the disease and difficulties in treatment. Schizophrenia is a particularly difficult disease to model in rodents due to the fact that it has a plethora of symptoms ranging from paranoia and delusions of grandeur to anhedonia and negative affect. The basis of these symptoms is believed to be due to neurochemical abnormalities and neuropathology in the brain, which most models have attempted to emulate. A brief review of findings regarding nicotine use and abuse in schizophrenics is presented, with findings using rodent models that have been able to provide insight into the mechanisms of addiction. A common clinical approach to the treatment of nicotine addiction in the schizophrenic population has been that these drugs are used for self-medication purposes, and it is clear that self-medication may actually be directed at several symptoms, including cognitive impairment and anhedonia. Finally, our laboratory has reported across a series of studies that neonatal treatment with the dopamine D2/D3 receptor agonist quinpirole results in long-term increases in dopamine-like receptor sensitivity, consistent with data reporting increases in dopamine D2 receptor function in schizophrenia. Across these studies, we have reported several behavioral, neurochemical, and genetic consistencies with the disease, and present a hypothesis for what we believe to be the basis of psychostimulant addiction in schizophrenia.

Neonatal quinpirole treatment enhances locomotor activation and dopamine release in the nucleus accumbens core in response to amphetamine treatment in adulthood

Neonatal quinpirole treatment to rats produces long‐term increases in D2 receptor sensitivity that persists throughout the animals lifetime, a phenomenon referred to as D2 priming. Male and female Sprague‐dawley rats were administered quinpirole (1 mg kg−1) or saline from postnatal days (P)1–11. At P60, all animals were given an injection of quinpirole (100 μg kg−1), and results showed that rats neonatally treated with quinpirole demonstrated enhanced yawning in response to quinprole, verifying D2 receptor priming because yawning is a D2 receptor mediated event. Beginning 1–3 days later, locomotor sensitization was tested through administration of d‐amphetamine (1 mg kg−1) or saline every other day over 14 days, and horizontal activity and turning behavior were analyzed. Findings indicated that D2‐priming enhanced horizontal activity in response to amphetamine in females compared to males at Days 1 and 4 of locomotor sensitization testing, and D2‐priming enhanced turning in response to amphetamine. Seven to ten days after sensitization was complete, microdialysis of the NAcc core was performed using a cumulative dosing regimen of amphetamine (0.1–3.0 mg kg−1). D2‐primed rats administered amphetamine demonstrated a 500% increase in accumbal DA overflow compared to control rats administered amphetamine. Additionally, amphetamine produced a significant increase in NE overflow compared to controls, but this was unaffected by D2 priming. These results indicate that D2 receptor priming as is produced by neonatal quinpirole treatment robustly enhances behavioral activation and accumbal DA overflow in response to amphetamine, which may underlie increases in psychostimulant use and abuse within the psychotic population where increased D2 receptor sensitivity is a hallmark. Synapse 64:289–300, 2010.

Sex differences in nicotine sensitization and conditioned hyperactivity in adolescent rats neonatally treated with quinpirole: role of D2 and D3 receptor subtypes.

Neonatal quinpirole treatment in rats produces increased sensitivity of dopamine D2-like receptors throughout the animals lifetime, referred to as D2 priming. There is little information on the effects of nicotine in adolescent rats, especially in a model that has clinical relevance to psychosis where increased D2 receptor sensitivity is common. Male and female rats were treated with quinpirole (1 mg/kg) or saline from postnatal (P) day 1-P21, given nicotine (0.5 mg/kg) or saline from P33 through P49, and placed into a locomotor arena for behavioral testing. Nicotine or saline treatment was preceded by the D2-like receptor antagonist eticlopride, D3 antagonist nafadotride, or saline. Conditioned hyperactivity was analyzed on P50 in the same context in a drug-free test. In females, D2 priming increased the locomotor response to acute nicotine, but did not affect subsequent nicotine sensitization, and only non-D2-primed females demonstrated conditioned hyperactivity. Eticlopride and nafadotride blocked behavioral sensitization, although nafadotride was more effective at blocking nicotine-conditioned hyperactivity in females. In males, D priming enhanced sensitization to nicotine and produced conditioned hyperactivity, which were blocked by eticlopride and nafadotride. These results have implications for psychosis and comorbidity of nicotine abuse in adolescence.

The Five‐Choice Continuous Performance Task (5C‐CPT): A Cross‐Species Relevant Paradigm for Assessment of Vigilance and Response Inhibition in Rodents

Deficits in the domains of attention and response inhibition are central to many psychiatric disorders. As such, animal models of disorders purporting to replicate these behavioral deficits first require tests that can accurately assess the behaviors with high fidelity. The gold-standard clinical test of attention and response inhibition is the continuous performance test (CPT). Although there are a number of CPTs, all share the premise of responding to target stimuli and inhibiting from responding to non-target stimuli. The recently developed rodent five-choice CPT (5C-CPT) requires similar behavioral responses, enabling signal detection parameter calculations. With demonstrable feasibility for rodent testing, the 5C-CPT permits/facilitates: (1) delineation of neural mechanisms underlying these behaviors; (2) multifactorial analyses of the complex interplay between genetic and environmental manipulations relevant to psychiatric disorders; and hence (3) development of novel targeted treatments. All data to date indicate that the rodent 5C-CPT described here has direct translatability to clinical CPTs, producing equivalent measures of behavior in experimental animals to those assessed in humans. The 5C-CPT task provides an important tool toward delineating these mechanisms and developing treatments. However, it is also complex, with long training times and nuances requiring a thorough understanding before utilization. This unit will enable researchers to avoid potential missteps, greatly increasing the likelihood of success.

Cognitive Phenotypes for Biomarker Identification in Mental Illness: Forward and Reverse Translation

Psychiatric illness has been acknowledged for as long as people were able to describe behavioral abnormalities in the general population. In modern times, these descriptions have been codified and continuously updated into manuals by which clinicians can diagnose patients. None of these diagnostic manuals have attempted to tie abnormalities to neural dysfunction however, nor do they necessitate the quantification of cognitive function despite common knowledge of its ties to functional outcome. In fact, in recent years the National Institute of Mental Health released a novel transdiagnostic classification, the Research Domain Criteria (RDoC), which utilizes quantifiable behavioral abnormalities linked to neurophysiological processes. This reclassification highlights the utility of RDoC constructs as potential cognitive biomarkers of disease state. In addition, with RDoC and cognitive biomarkers, the onus of researchers utilizing animal models no longer necessitates the recreation of an entire disease state, but distinct processes. Here, we describe the utilization of constructs from the RDoC initiative to forward animal research on these cognitive and behavioral processes, agnostic of disease. By linking neural processes to these constructs, identifying putative abnormalities in diseased patients, more targeted therapeutics can be developed.

Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression—how the same brain can switch between extreme states—described as the “holy grail” of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states.

Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse

Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of Gq-, but not Gs-signaling in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory Gi/o signaling in DA neurons blunted cocaine’s reinforcing and priming effects, reduced stress-potentiated reinstatement, and altered cue-induced cocaine seeking strategy, but not the motivational impact of cocaine cues per se. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein signaling, and DA neuron efferent target, highlighting their multifaceted roles in addiction. Significance Statement G-protein coupled receptors are crucial modulators of VTA dopamine neuron activity, but how metabotropic signaling impacts dopamine’s complex roles in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs during a variety of cocaine seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. Gq- and Gs-stimulation activated dopamine neurons, but only Gq stimulation robustly enhanced cocaine seeking. Gi/o inhibitory signaling altered the response strategy employed during cued reinstatement, and reduced some, but not all types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and indicate potential new approaches for intervening in these processes to treat addiction.

F38. WINTER-LIKE PHOTOPERIOD GESTATION DELETERIOUSLY AFFECT EXPERIENTIAL- BUT NOT EXPRESSIVE-RELATED BEHAVIORS, WHILE ADULT PHENCYCLIDINE TREATMENT INCREASES EXPERIENTIAL BEHAVIORS: RELEVANCE TO SCHIZOPHRENIA

Abstract Background Patients with schizophrenia exhibit negative symptoms that predict functional outcome. Understanding the mechanisms underlying these symptoms are important for developing novel therapeutic treatments. These negative symptoms can be grouped into experiential- (motivational) or expressive- (social) based behaviors testable in rodents. Increased incidences of schizophrenia have been reported with winter gestation, while antagonizing NMDA receptor function in adulthood has been used to model other symptoms of schizophrenia. These two approaches were used to determine mechanisms that may contribute to negative symptoms in schizophrenia and test potential therapeutics. Methods Normal dam mice were housed in custom photoperiod chambers for one week under normal photoperiod conditions (12 hour light:12 hour dark) to allow for initial acclimation. Half of the photoperiod chambers were then shifted to a short active (SA) condition (19 hours light: 5 hours dark) with mating triads formed. After a two-week pairing, pregnant dams were single-housed. The resulting pups were reared under these photoperiod conditions until P28, at which time they were weaned by sex into tetrads and moved into a standard vivarium room under normal active (NA) photoperiod. Mice were trained to perform nose-poke responses in a five-choice operant chamber. Adult Long Evans rats were also trained in separate 5-choice chambers and repeatedly treated with phencyclidine (PCP). Motivational behavior was tested on a progressive ratio breakpoint (PRB). Social behavior of mice were also assessed using a 3-chocie social recognition paradigm. Results In PRB, breakpoint was decreased in WT mice reared in SA vs. NA photoperiod (F(1,66)=4.4, p<0.05). In contrast however, no deficits in social interaction was observed (F<1, ns). Unlike the SA gestation-induced reduction in breakpoint, subchronic PCP increased breakpoint 1 [t(21)=5.3, p<0.0001], 7 [t(21)=2.2, p<0.0001] and 14 days after treatment to rats. Discussion Winter-like photoperiod births in mice induced psychiatry-relevant amotivation as measured by breakpoint, though did not affect social interaction or recognition. In contrast, subchronic PCP treatment increased breakpoint in rats tested 1 and 7 days after treatment. Hence, neurodevelopmental mechanisms underlying the winter-like gestation likely contribute to experiential- but not expressive-related behaviors, while altered NMDA receptor function are unlikely to contribute to such experiential-related abnormalities. Ongoing work will characterize epigenetic, synaptic, and/or system-level adaptations underlying developmental differences between NA and SA photoperiod born mice as well as defining critical periods throughout gestation and rearing that are driving these effects.

Dopamine transporter knockdown mice in the behavioral pattern monitor: A robust, reproducible model for mania-relevant behaviors

&NA; Efforts to replicate results from both basic and clinical models have highlighted problems with reproducibility in science. In psychiatry, reproducibility issues are compounded because the complex behavioral syndromes make many disorders challenging to model. We develop translatable tasks that quantitatively measure psychiatry‐relevant behaviors across species. The behavioral pattern monitor (BPM) was designed to analyze exploratory behaviors, which are altered in patients with bipolar disorder (BD), especially during mania episodes. We have repeatedly assessed the behavioral effects of reduced dopamine transporter (DAT) expression in the BPM using a DAT knockdown (KD) mouse line (˜ 10% normal expression). DAT KD mice exhibit a profile in the BPM consistent with acutely manic BD patients in the human version of the task—hyperactivity, increased exploratory behavior, and reduced spatial d (Perry et al., 2009). We collected data from multiple DAT KD BPM experiments in our laboratory to assess the reproducibility of behavioral outcomes across experiments. The four outcomes analyzed were: 1) transitions (amount of locomotor activity); 2) rearings (exploratory activity); 3) holepokes (exploratory activity); and 4) spatial d (geometrical pattern of locomotor activity). By comparing DAT KD mice to wildtype (WT) littermates in every experiment, we calculated effect sizes for each of the four outcomes and then calculated a mean effect size using a random effects model. DAT KD mice exhibited robust, reproducible changes in each of the four outcomes, including increased transitions, rearings, and holepokes, and reduced spatial d, vs. WT littermates. Our results demonstrate that the DAT KD mouse line in the BPM is a consistent, reproducible model of mania‐relevant behaviors. More work must be done to assess reproducibility of behavioral outcomes across experiments in order to advance the field of psychiatry and develop more effective therapeutics for patients.