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

The Drosophila and Manducahearts as models for studying the role of innervation in cardiac function

Cardiac activity of Drosophila melanogaster and Manduca sexta changes during metamorphosis. The larval heart has only anterograde contractions. Adult heart activity becomes a cyclic alternation of anterograde and retrograde contractions originated by putative anterograde and retrograde pacemakers. During development, the larval skeletal muscle motoneuron-1 in abdominal segments 7 and 8 becomes respecified to innervate the terminal cardiac chamber of adult Manduca and undergoes morphological and physiological reorganization. MNs-1 activate and sustain the anterograde pacemaker activity of the terminal chamber. The innervation of the adult abdominal heart of Drosophila melanogaster was studied to determine whether the adult heart receives neuronal input or whether its complex activity must be considered independent from the nervous system. The larval heart lacks innervation suggesting a myogenic cardiac impulse. At metamorphosis, neural processes grow onto the myocardium. A pair of glutamatergic transverse nerves innervates bilaterally each cardiac chamber. In addition, CCAP-immunoreactive fibers originating from peripheral, bipolar neurons (BpNs) fasciculate with the transverse nerve projections and terminate segmentally throughout the abdominal heart. To determine the role of this innervation in cardiac function, a novel optical technique based on the movement of GFP-labeled nerve terminals was developed to monitor heartbeat in intact preparations. Simultaneous monitoring of adjacent cardiac chambers revealed the direction of contractions and allowed correlation with volume changes. Intracellular recordings from the first abdominal cardiac chamber, the conical chamber, revealed pacemaker action potentials and the excitatory effect of local glutamate application. Bath-applied glutamate initiated retrograde contractions in semi-intact preparations. Similarly, electrical stimulation of the transverse nerve that serves the conical chamber caused a chronotropic effect and initiation of retrograde contractions. This effect is distinct from that of peripheral CCAP-immunoreactive neurons, which potentiate the anterograde beat. Cardiac reversal was evoked pharmacologically by sequentially applying CCAP and glutamate to the heart. The role of the neuropeptide, Crustacean Cardioactive Peptide (CCAP) in adult Drosophila melanogaster cardiac function was studied by RNA interference (RNAi) and targeted cell ablation. CCAP has a cardioacceleratory effect when it is applied in vitro. Lack of CCAP-innervation in CCAP knock-out flies altered one cardiac phase, the anterograde beat, without preventing the cyclic cardiac reversal

Investigating the mechanism(s) underlying switching between states in bipolar disorder.

Bipolar disorder (BD) is a unique disorder that transcends domains of function since the same patient can exhibit depression or mania, states with polar opposite mood symptoms. During depression, people feel helplessness, reduced energy, and risk aversion, while with mania behaviors include grandiosity, increased energy, less sleep, and risk preference. The neural mechanism(s) underlying each state are gaining clarity, with catecholaminergic disruption seen during mania, and cholinergic dysfunction during depression. The fact that the same patient cycles/switches between these states is the defining characteristic of BD however. Of greater importance therefore, is the mechanism(s) underlying cycling from one state - and its associated neural changes - to another, considered the 'holy grail' of BD research. Herein, we review studies investigating triggers that induce switching to these states. By identifying such triggers, researchers can study neural mechanisms underlying each state and importantly how such mechanistic changes can occur in the same subject. Current animal models of this switch are also discussed, from submissive- and dominant-behaviors to kindling effects. Focus however, is placed on how seasonal changes can induce manic and depressive states in BD sufferers. Importantly, changing photoperiod lengths can induce local switches in neurotransmitter expression in normal animals, from increased catecholaminergic expression during periods of high activity, to increased somatostatin and corticotrophin releasing factor during periods of low activity. Identifying susceptibilities to this switch would enable the development of targeted animal models. From animal models, targeted treatments could be developed and tested that would minimize the likelihood of switching