Nk Totah

Adolescent Behavior and Dopamine Availability Are Uniquely Sensitive to Dietary Omega-3 Fatty Acid Deficiency

BACKGROUND Understanding the nature of environmental factors that contribute to behavioral health is critical for successful prevention strategies in individuals at risk for psychiatric disorders. These factors are typically experiential in nature, such as stress and urbanicity, but nutrition--in particular dietary deficiency of omega-3 polyunsaturated fatty acids (n-3 PUFAs)-has increasingly been implicated in the symptomatic onset of schizophrenia and mood disorders, which typically occurs during adolescence to early adulthood. Thus, adolescence might be the critical age range for the negative impact of diet as an environmental insult. METHODS A rat model involving consecutive generations of n-3 PUFA deficiency was developed on the basis of the assumption that dietary trends toward decreased consumption of these fats began 4-5 decades ago when the parents of current adolescents were born. Behavioral performance in a wide range of tasks as well as markers of dopamine-related neurotransmission was compared in adolescents and adults fed n-3 PUFA adequate and deficient diets. RESULTS In adolescents, dietary n-3 PUFA deficiency across consecutive generations produced a modality-selective and task-dependent impairment in cognitive and motivated behavior distinct from the deficits observed in adults. Although this dietary deficiency affected expression of dopamine-related proteins in both age groups in adolescents but not adults, there was an increase in tyrosine hydroxylase expression that was selective to the dorsal striatum. CONCLUSIONS These data support a nutritional contribution to optimal cognitive and affective functioning in adolescents. Furthermore, they suggest that n-3 PUFA deficiency disrupts adolescent behaviors through enhanced dorsal striatal dopamine availability.

Unilateral electrical stimulation of rat locus coeruleus elicits bilateral response of norepinephrine neurons and sustained activation of medial prefrontal cortex.

The brain stem nucleus locus coeruleus (LC) is thought to modulate cortical excitability by norepinephrine (NE) release in LC forebrain targets. The effects of LC burst discharge, typically evoked by a strong excitatory input, on cortical ongoing activity are poorly understood. To address this question, we combined direct electrical stimulation of LC (LC-DES) with extracellular recording in LC and medial prefrontal cortex (mPFC), an important cortical target of LC. LC-DES consisting of single pulses (0.1-0.5 ms, 0.01-0.05 mA) or pulse trains (20-50 Hz, 50-200 ms) evoked short-latency excitatory and inhibitory LC responses bilaterally as well as a delayed rebound excitation occurring ∼100 ms after stimulation offset. The pulse trains, but not single pulses, reliably elicited mPFC activity change, which was proportional to the stimulation strength. The firing rate of ∼50% of mPFC units was significantly modulated by the strongest LC-DES. Responses of mPFC putative pyramidal neurons included fast (∼100 ms), transient (∼100-200 ms) inhibition (10% of units) or excitation (13%) and delayed (∼500 ms), sustained (∼1 s) excitation (26%). The sustained spiking resembled NE-dependent mPFC activity during the delay period of working memory tasks. Concurrently, the low-frequency (0.1-8 Hz) power of the local field potential (LFP) decreased and high-frequency (>20 Hz) power increased. Overall, the DES-induced LC firing pattern resembled the naturalistic biphasic response of LC-NE neurons to alerting stimuli and was associated with a shift in cortical state that may optimize processing of behaviorally relevant events.

Distinct prestimulus and poststimulus activation of VTA neurons correlates with stimulus detection

Dopamine neurons of the ventral tegmental area (VTA) signal the occurrence of a reward-predicting conditioned stimulus (CS) with a subsecond duration increase in post-CS firing rate. Important theories about reward-prediction error and reward expectancy have been informed by the substantial number of studies that have examined post-CS phasic VTA neuron activity. On the other hand, the role of VTA neurons in anticipation of a reward-predicting CS and analysis of prestimulus spike rate rarely has been studied. We recorded from the VTA in rats during the 3-choice reaction time task, which has a fixed-duration prestimulus period and a difficult-to-detect stimulus. Use of a stimulus that was difficult to detect led to behavioral errors, which allowed us to compare VTA activity between trials with correct and incorrect stimulus-guided choices. We found a sustained increase in firing rate of both putative dopamine and GABA neurons during the pre-CS period of correct and incorrect trials. The poststimulus phasic response, however, was absent on incorrect trials, suggesting that the stimulus-evoked phasic response of dopamine neurons may relate to stimulus detection. The prestimulus activation of VTA neurons may modulate cortical systems that represent internal states of stimulus expectation and provide a mechanism for dopamine neurotransmission to influence preparatory attention to an expected stimulus.

Atomoxetine accelerates attentional set shifting without affecting learning rate in the rat

RationaleShifting to a new rule is a form of behavioral flexibility that is impaired in numerous psychiatric and neurological illnesses. Animal studies have revealed that this form of flexibility depends upon norepinephrine (NE) neurotransmission. Atomoxetine, a NE reuptake inhibitor, improves performance of humans in set shifting tasks.ObjectiveOur objective was to validate its effects in a rodent set shifting task.MethodsWe tested the drug effect using an operant task that required a shift from a visual cue-guided behavior to a novel location-guided rule.ResultsA 1.0-mg/kg dose significantly accelerated rule shifting without affecting learning strategies, such as win-stay or lose-shift. Fitting behavioral performance with a learning function provided a measure of learning rate.ConclusionThis novel analysis revealed that atomoxetine accelerated shifting to the new rule without affecting learning rate.

Monitoring large populations of locus coeruleus neurons reveals the non-global nature of the norepinephrine neuromodulatory system

The non-specific neuromodulation of the forebrain by the noradrenergic locus coeruleus (LC) is a foundation of wide-ranging theories of cognitive and systems neuroscience. The non-specificity is assumed because of the diffuse projections of the nucleus as well as the synchronous spiking of its neurons. Synchrony, however, has never been assessed in a large population of LC cells, i.e. single units, nor has it been systematically related to specificity of their projection targets. Here, we recorded up to 52 single units simultaneously (3164 unit pairs) in the rat LC, and characterized forebrain projection patterns using antidromic stimulation. Two novel unit types were characterized; they differed by waveform shape, firing rate, and propensity for synchronization. Cross-correlation analysis revealed a surprisingly poor correlation between unit spiking; only 13% of unit pairs had response profiles reflecting synchronization due to common synaptic input or gap junctions. While LC unit spikes were phase locked to cortical slow oscillations (< 2 Hz), they did so intermittently, yielding poor population synchronization. A novel infra-slow (0.01-1 Hz) spiking fluctuation was observed in LC units, yet this too was asynchronous across unit pairs. A highly synchronized minority had a stronger tendency for targeted forebrain neuromodulation. Our findings demonstrate that the LC may convey a more complex and differentiated neuromodulatory signal than is widely assumed.