The brain reward circuit has a central role in reinforcing behaviors that are rewarding and preventing behaviors that lead to punishment. Recent work has shown that the lateral habenula is an ...important part of the reward circuit by providing 'negative value' signals to the dopaminergic and serotonergic systems. Studies have also suggested that dysfunction of the lateral habenula is associated with psychiatric disorders, including major depression. Here, we discuss insights gained from neuronal recordings in monkeys regarding how the lateral habenula processes reward-related information. We then highlight recent optogenetic experiments in rodents addressing normal and abnormal functions of the habenula. Finally, we discuss how deregulation of the lateral habenula may be involved in depressive behaviors.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The lateral habenula (LHb) has recently been identified as a key regulator of the reward system by driving inhibition onto dopaminergic neurons. However, the nature and potential modulation of the ...major input to the LHb originating from the basal ganglia are poorly understood. Although the output of the basal ganglia is thought to be primarily inhibitory, here we show that transmission from the basal ganglia to the LHb is excitatory, glutamatergic, and suppressed by serotonin. Behaviorally, activation of this pathway is aversive, consistent with its role as an “antireward” signal. Our demonstration of an excitatory projection from the basal ganglia to the LHb explains how LHb-projecting basal ganglia neurons can have similar encoding properties as LHb neurons themselves. Our results also provide a link between antireward excitatory synapses and serotonin, a neuromodulator implicated in depression.
► Input to the lateral habenula from the basal ganglia is excitatory ► Excitatory input to the lateral habenula from the basal ganglia is glutamatergic ► Input to the lateral habenula from the basal ganglia is aversive ► Serotonin suppresses excitatory input to the LHb from the basal ganglia
Shabel et al. characterize a major input to the lateral habenula, a brain region involved in reward, and show that this input is aversive and suppressed by serotonin, providing a link between aversive signaling and a neuromodulator involved in depression.
The lateral habenula (LHb), a key regulator of monoaminergic brain regions, is activated by negatively valenced events. Its hyperactivity is associated with depression. Although enhanced excitatory ...input to the LHb has been linked to depression, little is known about inhibitory transmission. We discovered that γ-aminobutyric acid (GABA) is co-released with its functional opponent, glutamate, from long-range basal ganglia inputs (which signal negative events) to limit LHb activity in rodents. At this synapse, the balance of GABA/glutamate signaling is shifted toward reduced GABA in a model of depression and increased GABA by antidepressant treatment. GABA and glutamate co-release therefore controls LHb activity, and regulation of this form of transmission may be important for determining the effect of negative life events on mood and behavior.
Abstract Background Major depressive disorder is associated with disturbed circadian rhythms. To investigate the causal relationship between mood disorders and circadian clock disruption, previous ...studies in animal models have employed light-dark manipulations, global mutations of clock genes, or brain area lesions. However, light can impact mood by non-circadian mechanisms, clock genes have pleiotropic, clock-independent functions, and brain lesions not only disrupt cellular circadian rhythms but also destroy cells and eliminate important neuronal connections, including light reception pathways. Thus, a definitive causal role for functioning circadian clocks in mood regulation has not been established. Methods In this study, we stereotaxically injected viral vectors encoding shRNA to knock down expression of the essential clock gene Bmal1 into the brain’s master circadian pacemaker, the suprachiasmatic nucleus (SCN). Results In these SCN-specific Bmal1 -knockdown (SCN- Bmal1 -KD) mice, circadian rhythms are greatly attenuated in the SCN, while the mice are maintained in a standard light/dark cycle, SCN neurons remain intact, and neuronal connections are undisturbed, including photic inputs. In the learned helplessness paradigm, these mice are slower to escape, even before exposure to inescapable stress. They also spend more time immobile in the tail suspension test and less time in the lighted section of a light/dark box. SCN- Bmal1 -KD mice also show greater weight gain, an abnormal circadian pattern of corticosterone, and an attenuated increase of corticosterone in response to stress. Conclusion Thus, disrupting SCN circadian rhythms is sufficient to cause helplessness, behavioral despair, and anxiety-like behavior in mice, establishing SCN- Bmal1 -KD mice as a new animal model of depression.
Optogenetic techniques provide effective ways of manipulating the functions of selected neurons with light. In the current study, we engineered an optogenetic technique that directly inhibits ...neurotransmitter release. We used a genetically encoded singlet oxygen generator, miniSOG, to conduct chromophore assisted light inactivation (CALI) of synaptic proteins. Fusions of miniSOG to VAMP2 and synaptophysin enabled disruption of presynaptic vesicular release upon illumination with blue light. In cultured neurons and hippocampal organotypic slices, synaptic release was reduced up to 100%. Such inhibition lasted >1 hr and had minimal effects on membrane electrical properties. When miniSOG-VAMP2 was expressed panneuronally in Caenorhabditis elegans, movement of the worms was reduced after illumination, and paralysis was often observed. The movement of the worms recovered overnight. We name this technique Inhibition of Synapses with CALI (InSynC). InSynC is a powerful way to silence genetically specified synapses with light in a spatially and temporally precise manner.
•MiniSOG mediates CALI of presynaptic release proteins•Synaptic release is inhibited optogenetically with miniSOG fused VAMP2 or SYP1•Light reversibly reduces movement in miniSOG-VAMP2-expressing C. elegans
Lin et al. tether miniSOG to presynaptic proteins allowing optogenetic inhibition of synaptic release. This technique, InSynC, effectively inhibits synapses in cultured neurons, organotypic slice, and behaving C. elegans and is useful for studying the function of specific projections.
The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain ...and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recording the activity of a group of neurons in a freely-moving animal is a challenging undertaking. Moreover, as the brain is dissected into smaller and smaller functional subgroups, it becomes ...paramount to record from projections and/or genetically-defined subpopulations of neurons. Fiber photometry is an accessible and powerful approach that can overcome these challenges. By combining optical and genetic methodologies, neural activity can be measured in deep brain structures by expressing genetically-encoded calcium indicators, which translate neural activity into an optical signal that can be easily measured. The current protocol details the components of a multi-fiber photometry system, how to access deep brain structures to deliver and collect light, a method to account for motion artifacts, and how to process and analyze fluorescent signals. The protocol details experimental considerations when performing single and dual color imaging, from either single or multiple implanted optic fibers.
A neural pathway controlling motivation to exert effort Proulx, Christophe D.; Aronson, Sage; Milivojevic, Djordje ...
Proceedings of the National Academy of Sciences - PNAS,
05/2018, Letnik:
115, Številka:
22
Journal Article
Recenzirano
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The neural mechanisms conferring reduced motivation, as observed in depressed individuals, is poorly understood. Here, we examine in rodents if reduced motivation to exert effort is controlled by ...transmission from the lateral habenula (LHb), a nucleus overactive in depressed-like states, to the rostromedial tegmental nucleus (RMTg), a nucleus that inhibits dopaminergic neurons. In an aversive test wherein immobility indicates loss of effort, LHb→RMTg transmission increased during transitions into immobility, driving LHb→RMTg increased immobility, and inhibiting LHb→RMTg produced the opposite effects. In an appetitive test, driving LHb→RMTg reduced the effort exerted to receive a reward, without affecting the reward’s hedonic property. Notably, LHb→RMTg stimulation only affected specific aspects of these motor tasks, did not affect all motor tasks, and promoted avoidance, indicating that LHb→RMTg activity does not generally reduce movement but appears to carry a negative valence that reduces effort. These results indicate that LHb→RMTg activity controls the motivation to exert effort and may contribute to the reduced motivation in depression.
Engineering a memory with LTD and LTP Nabavi, Sadegh; Fox, Rocky; Proulx, Christophe D ...
Nature,
07/2014, Letnik:
511, Številka:
7509
Journal Article
Recenzirano
Odprti dostop
It has been proposed that memories are encoded by modification of synaptic strengths through cellular mechanisms such as long-term potentiation (LTP) and long-term depression (LTD). However, the ...causal link between these synaptic processes and memory has been difficult to demonstrate. Here we show that fear conditioning, a type of associative memory, can be inactivated and reactivated by LTD and LTP, respectively. We began by conditioning an animal to associate a foot shock with optogenetic stimulation of auditory inputs targeting the amygdala, a brain region known to be essential for fear conditioning. Subsequent optogenetic delivery of LTD conditioning to the auditory input inactivates memory of the shock. Then subsequent optogenetic delivery of LTP conditioning to the auditory input reactivates memory of the shock. Thus, we have engineered inactivation and reactivation of a memory using LTD and LTP, supporting a causal link between these synaptic processes and memory.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Locking away depression Silva, Jose Cesar Hernandez; Proulx, Christophe D.
Science (American Association for the Advancement of Science),
08/2024, Letnik:
385, Številka:
6709
Journal Article
Recenzirano
The antidepressant ketamine blocks neuroreceptors in hyperactive brain regions
Approximately 280 million people worldwide suffer from depression, which affects all aspects of life and is a leading ...cause of suicide ( 1 ). Although traditional antidepressants (which act on monoamine neurotransmitters, such as serotonin and dopamine) can offer relief, they often take several weeks to become effective and many patients do not achieve sustained remission. Ketamine emerged as a revolutionary antidepressant owing to its rapid onset and sustained efficacy. Although ketamine is a noncompetitive blocker (antagonist) of N -methyl-D-aspartate receptor (NMDAR), the mechanisms by which it exerts its antidepressant effects remain unclear. On page 621 of this issue, Chen et al . ( 2 ) report that ketamine locks NMDARs in an inactive state, particularly in hyperactive neurons of the lateral habenula (LHb), blocking neuronal bursting activity and alleviating depressive symptoms in mice. The findings provide a mechanistic basis for ketamine’s rapid, region-specific, and sustained effects and could facilitate the design of improved antidepressants.
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