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Linking context with reward: a functional circuit from hippocampal CA3 to ventral tegmental area.
Science. 2011 Jul 15; 333(6040):353-7
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02 Aug 2011
New Finding
DOI: 10.3410/f.12250956.13526054
In this study, Luo and coauthors provide evidence for a previously unknown pathway from area CA3 of the dorsal hippocampus (HPC) to the ventral tegmental area (VTA), functionally linking the processing of contextual information with rewarding outcomes.
Using pseudo-rabies virus for retrograde, transynaptic...Continue reading
Using pseudo-rabies virus for retrograde, transynaptic...Continue reading
In this study, Luo and coauthors provide evidence for a previously unknown pathway from area CA3 of the dorsal hippocampus (HPC) to the ventral tegmental area (VTA), functionally linking the processing of contextual information with rewarding outcomes.
Using pseudo-rabies virus for retrograde, transynaptic tracing, they show that dorsal CA3 neurons project to GABAergic neurons in the caudodorsal lateral septum, which in turn project to GABAergic neurons in the VTA, locally regulating dopamine neuron firing. Functional inactivation of each of these 3 nodes inhibits context-induced reinstatement of cocaine seeking. This study provides evidence for a novel HPC-VTA pathway operating independent of a previously known pathway originating from the ventral subiculum. Future studies dissociating the relative contribution of each of these hippocampal output pathways to either context-reward associations or to motivated behavior will provide important insight into how the hippocampus contributes to cognitive and affective behaviors.
Using pseudo-rabies virus for retrograde, transynaptic tracing, they show that dorsal CA3 neurons project to GABAergic neurons in the caudodorsal lateral septum, which in turn project to GABAergic neurons in the VTA, locally regulating dopamine neuron firing. Functional inactivation of each of these 3 nodes inhibits context-induced reinstatement of cocaine seeking. This study provides evidence for a novel HPC-VTA pathway operating independent of a previously known pathway originating from the ventral subiculum. Future studies dissociating the relative contribution of each of these hippocampal output pathways to either context-reward associations or to motivated behavior will provide important insight into how the hippocampus contributes to cognitive and affective behaviors.
Disclosures
None declared
Add Comment
Hen R and Kheirbek M: F1000Prime Recommendation of [Luo AH et al., Science 2011, 333(6040):353-7]. In F1000Prime, 02 Aug 2011; DOI: 10.3410/f.12250956.13526054. F1000Prime.com/12250956#eval13526054
27 Oct 2011
New Finding
DOI: 10.3410/f.12250956.13422054
This article demonstrates, through the employment of a variety of techniques, a novel circuit from area CA3 to the ventral tegmental area (VTA) via the caudodorsal lateral septum (cd-LS), providing intriguing insights into how the memory and reward networks of the brain communicate.
It is well established...Continue reading
It is well established...Continue reading
This article demonstrates, through the employment of a variety of techniques, a novel circuit from area CA3 to the ventral tegmental area (VTA) via the caudodorsal lateral septum (cd-LS), providing intriguing insights into how the memory and reward networks of the brain communicate.
It is well established that the VTA plays a fundamental role in signalling reward {1} and novelty {2}, while the hippocampus is known to support relational memory formation {3} and novelty detection {4}. Although the functions of these two structures seem intrinsically linked, the means by which the two communicate has remained unclear.
Luo et al. demonstrated, through a variety of techniques, an indirect circuit from area CA3 of the hippocampus to the VTA via the cd-LS. The authors first used a transsynaptic tracer (pseudorabies virus [PRV]) to delineate this pathway. PRV injections into VTA resulted in PRV(+) neurons in ventral, intermediate and dorsal CA2/CA3 at 48 hours post injection. The time course of PRV labelling suggested an indirect pathway, as no labelling was observed in CA3 at a shorter time delay of 36 hours, at which PRV(+) neurons were seen in abundance in the cd-LS. In fact, cd-LS showed the largest number of PRV labelling at this time point. Thus, to investigate whether cd-LS mediates projections from CA3 to VTA, cd-LS cell bodies were lesioned using ibotenic acid 5-7 days prior to PRV injections. Consistent with CA3 projecting directly to cd-LS, the lesion resulted in more than 80% decrease of PRV labelling in dorsal CA3.
To examine this newly found pathway further, single-unit activity of VTA neurons was recorded in urethane-anesthetised rats while CA3 was electrically stimulated. Of all recorded neurons, 86% responded to stimulation. Responses fell into two categories: sustained excitation (E-E) or sustained inhibition (I-I). E-E neurons were confirmed as dopamine (DA) neurons, while I-I neurons showed the electrophysiological characteristics of gamma-aminobutyric acid (GABA) neurons. To investigate the role of cd-LS in mediating VTA activity in response to CA3 stimulation, the authors transiently inactivated cd-LS using local microinjection of GABA during the CA3 stimulation. This reversibly blocked both E-E and I-I responses in the VTA. The authors demonstrated that the excitatory effect of CA3 stimulation on DA neurons is driven by inhibition of GABA neurons by blocking the effect of stimulation via local injection of a GABA antagonist.
Finally, the authors investigated the behavioural implications of the CA3-cd-LS-VTA circuit using a contextual conditioning task. Rats were initially trained to self-administer cocaine in one context, while in a second one they underwent extinction training. Rats were then put back in the original context, so to reinstate the extinguished response. Luo et al. found that, in CA3-lesioned as well as in cd-LS- and contralaterally VTA-lesioned animals, this context-induced reinstatement was blocked.
In sum, Luo et al. have rigorously demonstrated a novel circuit that connects the CA3 memory network with the VTA reward network, elucidating the means by which context can be linked with reward. Perhaps future research could clarify the role that this pathway plays in the proposed comparator function of area CA1 {5}.
It is well established that the VTA plays a fundamental role in signalling reward {1} and novelty {2}, while the hippocampus is known to support relational memory formation {3} and novelty detection {4}. Although the functions of these two structures seem intrinsically linked, the means by which the two communicate has remained unclear.
Luo et al. demonstrated, through a variety of techniques, an indirect circuit from area CA3 of the hippocampus to the VTA via the cd-LS. The authors first used a transsynaptic tracer (pseudorabies virus [PRV]) to delineate this pathway. PRV injections into VTA resulted in PRV(+) neurons in ventral, intermediate and dorsal CA2/CA3 at 48 hours post injection. The time course of PRV labelling suggested an indirect pathway, as no labelling was observed in CA3 at a shorter time delay of 36 hours, at which PRV(+) neurons were seen in abundance in the cd-LS. In fact, cd-LS showed the largest number of PRV labelling at this time point. Thus, to investigate whether cd-LS mediates projections from CA3 to VTA, cd-LS cell bodies were lesioned using ibotenic acid 5-7 days prior to PRV injections. Consistent with CA3 projecting directly to cd-LS, the lesion resulted in more than 80% decrease of PRV labelling in dorsal CA3.
To examine this newly found pathway further, single-unit activity of VTA neurons was recorded in urethane-anesthetised rats while CA3 was electrically stimulated. Of all recorded neurons, 86% responded to stimulation. Responses fell into two categories: sustained excitation (E-E) or sustained inhibition (I-I). E-E neurons were confirmed as dopamine (DA) neurons, while I-I neurons showed the electrophysiological characteristics of gamma-aminobutyric acid (GABA) neurons. To investigate the role of cd-LS in mediating VTA activity in response to CA3 stimulation, the authors transiently inactivated cd-LS using local microinjection of GABA during the CA3 stimulation. This reversibly blocked both E-E and I-I responses in the VTA. The authors demonstrated that the excitatory effect of CA3 stimulation on DA neurons is driven by inhibition of GABA neurons by blocking the effect of stimulation via local injection of a GABA antagonist.
Finally, the authors investigated the behavioural implications of the CA3-cd-LS-VTA circuit using a contextual conditioning task. Rats were initially trained to self-administer cocaine in one context, while in a second one they underwent extinction training. Rats were then put back in the original context, so to reinstate the extinguished response. Luo et al. found that, in CA3-lesioned as well as in cd-LS- and contralaterally VTA-lesioned animals, this context-induced reinstatement was blocked.
In sum, Luo et al. have rigorously demonstrated a novel circuit that connects the CA3 memory network with the VTA reward network, elucidating the means by which context can be linked with reward. Perhaps future research could clarify the role that this pathway plays in the proposed comparator function of area CA1 {5}.
References
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Multiple dopamine functions at different time courses.
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PMID: 17600522
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Responses of monkey dopamine neurons during learning of behavioral reactions.
J Neurophysiol 1992 Jan; 1(67):145-63
PMID: 1552316
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Hippocampus: cognitive processes and neural representations that underlie declarative memory.
Neuron 2004 Sep 30; 1(44):109-20
PMID: 15450164
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Hippocampal neurons responding to first-time dislocation of a target object.
Neuron 2002 Aug 1; 3(35):555-66
PMID: 12165476
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The hippocampal-VTA loop: controlling the entry of information into long-term memory.
Neuron 2005 Jun 2; 5(46):703-13
PMID: 15924857
Disclosures
None declared
Spiers H and Olafsdottir H: F1000Prime Recommendation of [Luo AH et al., Science 2011, 333(6040):353-7]. In F1000Prime, 27 Oct 2011; DOI: 10.3410/f.12250956.13422054. F1000Prime.com/12250956#eval13422054
F1000Prime Recommendations, Dissents and Comments for [Luo AH et al., Science 2011, 333(6040):353-7]. In F1000Prime, 25 May 2013; F1000Prime.com/12250956
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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.
PMID: 21764750
