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

Single neuron transcriptomics identify SRSF/ SR protein B52 as a regulator of axon growth and Choline acetyltransferase splicing.

We removed single identified neurons from living Drosophila embryos to gain insight into the transcriptional control of developing neuronal networks. The microarray analysis of the transcriptome of two sibling neurons revealed seven differentially expressed transcripts between both neurons (threshold: log(2)1.4). One transcript encodes the RNA splicing factor B52. Loss of B52 increases growth of axon branches. B52 function is also required for Choline acetyltransferase (ChAT ) splicing. At the end of embryogenesis, loss of B52 function impedes splicing of ChAT, reduces acetylcholine synthesis, and extends the period of uncoordinated muscle twitches during larval hatching. ChAT regulation by SRSF proteins may be a conserved feature since changes in SRSF5 expression and increased acetylcholine levels in brains of bipolar disease patients have been reported recently

Cross-Species Studies on the Mechanisms Underlying Abnormal Behavior in Bipolar Disorder: A Dopaminergic Focus

Bipolar disorder (BD) is a severe neuropsychiatric disorder, affecting approximately 2% of the worldwide population. It is characterized by euphoric states of mania and opposite mood states of depression, which are devastating to the patients’ quality of life. Current treatment options are poor and may contribute to 1 in 3 patients attempting suicide. This shortage of efficacious therapeutics may be due to their serendipitous origin. Hence, neurocognitive symptoms often go untreated, while being highly associated with one’s functional outcome. Novel medication targeted at the disease is therefore urgently required. To better understand BD and develop targeted treatments, better animal models for BD with etiological and pharmacological validity are needed. This thesis describes a combination of approaches, investigating the putative underlying mechanisms of BD and providing novel targets to aid treatment development. Dysfunctional dopamine (DA) neurotransmission caused by reduced DA transporter (DAT) functioning likely plays a central role in the pathophysiology. Previously, BD patients exhibited a characteristic pattern in a human behavioral pattern monitor (BPM). Here, we observed that DAT knockdown (KD) mice exhibited the same hyperactive and hyper-explorative pattern in the mouse BPM. Catecholamine depletion with alpha-methyl-p-tyrosine (AMPT) attenuated some of these abnormalities. Selective DAT inhibition with GBR12909 also induced this BPM pattern and resulted in prepulse inhibition (PPI) deficits. Chronic valproate (mood-stabilizer) partly attenuated this BPM pattern in both DAT models. Chronic lithium however, exaggerated abnormal BPM behavior in the GBR12909 model, but normalized PPI deficits. Besides abnormal exploratory behavior, novel BD treatments should also target neurocognitive deficits. Both DAT models exhibited impaired decision-making in a mouse Iowa gambling task (IGT) consistent with BD patients. Moreover, increased motivation and motor impulsivity indicative of increased hedonia in BD were observed. DAT KD mice also exhibited reduced vigilance in an attentional task consistent with poor vigilance of BD patients. Finally, sleep deprivation impaired attention similarly in normal mice and healthy humans. Hence, these data highlight that reduced DAT functioning can reproduce abnormal exploration, PPI deficits, and cognitive deficits associated with BD mania. To investigate factors contributing to BD depression, we assessed the effects of acetylcholine-esterase (AChE) inhibition in mice. Physostigmine induced depressive-like behavior which was attenuated by chronic lithium. Because abnormal circadian rhythms are also present in patients, we tested mice with disrupted circadian rhythms (Clock∆19) and observed hyperactivity and hyper-exploration in the BPM, PPI deficits in the acoustic startle test, and increased saccharine preference. Further assessment of these mice as model animals for BD is warranted. Ultimately, these studies highlight the need to look beyond DATs and mania alone in investigating and treating BD. In conclusion, this thesis provides further information on the underlying mechanisms of different phases of BD and offers a way to test novel therapeutics. Dysfunctional DATs and disrupted circadian rhythms mediate mania-like behavior, while cholinergic systems are likely more important in depression. Utilizing extensively validated animal models with etiological and predictive validity as described in this thesis may ultimately yield therapeutics that specifically target the underlying circuitry of BD and improve the lives of patients

Cross-Species Studies on the Mechanisms Underlying Abnormal Behavior in Bipolar Disorder: A Dopaminergic Focus

Bipolar disorder (BD) is a severe neuropsychiatric disorder, affecting approximately 2% of the worldwide population. It is characterized by euphoric states of mania and opposite mood states of depression, which are devastating to the patients’ quality of life. Current treatment options are poor and may contribute to 1 in 3 patients attempting suicide. This shortage of efficacious therapeutics may be due to their serendipitous origin. Hence, neurocognitive symptoms often go untreated, while being highly associated with one’s functional outcome. Novel medication targeted at the disease is therefore urgently required. To better understand BD and develop targeted treatments, better animal models for BD with etiological and pharmacological validity are needed. This thesis describes a combination of approaches, investigating the putative underlying mechanisms of BD and providing novel targets to aid treatment development. Dysfunctional dopamine (DA) neurotransmission caused by reduced DA transporter (DAT) functioning likely plays a central role in the pathophysiology. Previously, BD patients exhibited a characteristic pattern in a human behavioral pattern monitor (BPM). Here, we observed that DAT knockdown (KD) mice exhibited the same hyperactive and hyper-explorative pattern in the mouse BPM. Catecholamine depletion with alpha-methyl-p-tyrosine (AMPT) attenuated some of these abnormalities. Selective DAT inhibition with GBR12909 also induced this BPM pattern and resulted in prepulse inhibition (PPI) deficits. Chronic valproate (mood-stabilizer) partly attenuated this BPM pattern in both DAT models. Chronic lithium however, exaggerated abnormal BPM behavior in the GBR12909 model, but normalized PPI deficits. Besides abnormal exploratory behavior, novel BD treatments should also target neurocognitive deficits. Both DAT models exhibited impaired decision-making in a mouse Iowa gambling task (IGT) consistent with BD patients. Moreover, increased motivation and motor impulsivity indicative of increased hedonia in BD were observed. DAT KD mice also exhibited reduced vigilance in an attentional task consistent with poor vigilance of BD patients. Finally, sleep deprivation impaired attention similarly in normal mice and healthy humans. Hence, these data highlight that reduced DAT functioning can reproduce abnormal exploration, PPI deficits, and cognitive deficits associated with BD mania. To investigate factors contributing to BD depression, we assessed the effects of acetylcholine-esterase (AChE) inhibition in mice. Physostigmine induced depressive-like behavior which was attenuated by chronic lithium. Because abnormal circadian rhythms are also present in patients, we tested mice with disrupted circadian rhythms (Clock∆19) and observed hyperactivity and hyper-exploration in the BPM, PPI deficits in the acoustic startle test, and increased saccharine preference. Further assessment of these mice as model animals for BD is warranted. Ultimately, these studies highlight the need to look beyond DATs and mania alone in investigating and treating BD. In conclusion, this thesis provides further information on the underlying mechanisms of different phases of BD and offers a way to test novel therapeutics. Dysfunctional DATs and disrupted circadian rhythms mediate mania-like behavior, while cholinergic systems are likely more important in depression. Utilizing extensively validated animal models with etiological and predictive validity as described in this thesis may ultimately yield therapeutics that specifically target the underlying circuitry of BD and improve the lives of patients

Nicotine withdrawal-induced inattention is absent in alpha7 nAChR knockout mice.

RationaleSmoking is the leading cause of preventable death in the USA, but quit attempts result in withdrawal-induced cognitive dysfunction and predicts relapse. Greater understanding of the neural mechanism(s) underlying these cognitive deficits is required to develop targeted treatments to aid quit attempts.ObjectivesWe examined nicotine withdrawal-induced inattention in mice lacking the α7 nicotinic acetylcholine receptor (nAChR) using the five-choice continuous performance test (5C-CPT).MethodsMice were trained in the 5C-CPT prior to osmotic minipump implantation containing saline or nicotine. Experiment 1 used 40 mg kg-1 day-1 nicotine treatment and tested C57BL/6 mice 4, 28, and 52 h after pump removal. Experiment 2 used 14 and 40 mg kg-1 day-1 nicotine treatment in α7 nAChR knockout (KO) and wildtype (WT) littermates tested 4 h after pump removal. Subsets of WT mice were killed before and after pump removal to assess changes in receptor expression associated with nicotine administration and withdrawal.ResultsNicotine withdrawal impaired attention in the 5C-CPT, driven by response inhibition and target detection deficits. The overall attentional deficit was absent in α7 nAChR KO mice despite response disinhibition in these mice. Synaptosomal glutamate mGluR5 and dopamine D4 receptor expression were reduced during chronic nicotine but increased during withdrawal, potentially contributing to cognitive deficits.ConclusionsThe α7 nAChR may underlie nicotine withdrawal-induced deficits in target detection but is not required for response disinhibition deficits. Alterations to the glutamatergic and dopaminergic pathways may also contribute to withdrawal-induced attentional deficits, providing novel targets to alleviate the cognitive symptoms of withdrawal during quit attempts