Scientific Understanding of Consciousness
Hippocampal CA3 Link to Ventral Tegmental Area
Science 15 July 2011: Vol. 333 no. 6040 pp. 353-357
Alice H. Luo1, Pouya Tahsili-Fahadan2, Roy A. Wise1, Carl R. Lupica3, Gary Aston-Jones2
1Behavioral Neuroscience Section, Behavioral Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
2Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
3Electrophysiology Research Section, Cellular Neurobiology Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Reward-motivated behavior is strongly influenced by the learned significance of contextual stimuli in the environment. However, the neural pathways that mediate context-reward relations are not well understood. We have identified a circuit from area CA3 of dorsal hippocampus to ventral tegmental area (VTA) that uses lateral septum (LS) as a relay. Theta frequency stimulation of CA3 excited VTA dopamine (DA) neurons and inhibited non-DA neurons. DA neuron excitation was likely mediated by disinhibition because local antagonism of γ-aminobutyric acid receptors blocked responses to CA3 stimulation. Inactivating components of the CA3-LS-VTA pathway blocked evoked responses in VTA and also reinstatement of cocaine-seeking by contextual stimuli. This transsynaptic link between hippocampus and VTA appears to be an important substrate by which environmental context regulates goal-directed behavior.
Efficient reward-seeking requires that environmental stimuli be properly interpreted, to predict when and where reward can be expected. The ventral tegmental area (VTA) and its dopaminergic projections are critical components of a reward circuit. Although the influence of temporal cues on this system has been well studied, it is unknown how the VTA system relates to other contextual information, such as where reward can be expected. The hippocampus organizes aspects of context into a relational memory network. Interactions between hippocampus and VTA are important for context-reward associations. However, the circuitry by which the two interact remains to be elucidated.
We used pseudo-rabies virus (PRV), a retrograde, transsynaptic tracer, to delineate circuit projections to VTA.
VTA GABA neurons normally hold their DA neighbors under tonic inhibition. Therefore, we hypothesized that the excitation of DA neurons was a secondary consequence of the inhibition of non-DA (presumed GABA) VTA neurons. To test this hypothesis, a mixture of GABA receptor antagonists (picrotoxin-CGP55845) was microinjected onto the recorded VTA neuron during CA3 stimulation. Excitation (paired t test, P = 0.01) and inhibition (P = 0.04) of VTA neurons by CA3 theta stimulation were each blocked. This blockade occurred for responses in all tested cell categories.
The hippocampus is important for its ability to use contextual information to regulate behavior, including drug-seeking. Furthermore, VTA DA neurons are critical for the rewarding effects of cocaine and the reinstatement of cocaine-seeking after abstinence or extinction training. Therefore, we tested whether inactivating components of this pathway would interfere with context-induced reinstatement of extinguished cocaine-seeking. Inactivation of dorsal CA3 via bilateral infusion of the GABA agonists baclofen and muscimol (B-M) blocked context-induced reinstatement of active lever pressing. We also tested the role of the cd-LS–to–VTA component of the pathway. Injections of B-M into cd-LS in one hemisphere and into VTA in the contralateral hemisphere of the same animal also blocked reinstatement
Our working model of the dorsal CA3–cd-LS–VTA pathway response to hippocampal theta rhythm is outlined. We propose that a population cd-LS GABA neurons project to VTA GABA neurons and that stimulation of CA3 glutamatergic pyramidal neurons excites these GABAergic cd-LS neurons, which results in inhibition of VTA GABA (I-I) neurons. Under basal conditions, VTA GABA neurons tonically inhibit VTA DA neurons; therefore, removal of local GABA inhibition by cd-LS activity would be expected to disinhibit VTA DA (E-E) neurons. This effect is proposed to contribute to context-induced modulation of motivated behaviors. Although the specific relation between CA3 theta rhythm, VTA dopamine neuron excitation, and context-dependent regulation of behavior remains unknown, our results establish fundamental characteristics of this circuit and its significance in physiology and behavior. On the basis of our anatomical and electrophysiological data, our dorsal CA3-to-VTA pathway appears to be independent of the previously reported hippocampus-to-VTA pathway originating in vSUB.
Our results show that this dorsal CA3–cd-LS–VTA pathway is an important conduit by which contextual information reaches the midbrain DA system for regulation of motivational behaviors. Our pathway may be involved in the processing of context-reward associations, in both normative function and disease states. Recent work has shown that CA3 place cells react more to global, rather than local, changes in the environment, and the role of midbrain DA neurons in salience attribution is increasingly appreciated. It is possible that dorsal CA3 conveys information to VTA about the current context as a whole, which allows rapid activation of DA neurons to promote salience attribution to conditioned contexts. Such processing is important for cognitive function by providing adjustments in behavior in response to changing real-world environments.
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