The Role of the Endocannabinoid System in Learning-Induced Neurogenesis

Though it was previously thought that the birth of new neurons stopped after development, we now know that neurogenesis continues throughout life in some areas of the brain (i.e. the olfactory bulb and the dentate gyrus of the hippocampus). Learning, in particular, has been shown to facilitate the survival of newborn neurons in the dentate gyrus. The endocannabinoid system, famous for its activation by the illicit drug cannabis (marijuana), is known to play a role in learning as well as both developmental and normal adult hippocampal neurogenesis. This study aimed to test whether the role of the endocannabinoid system extends to the specific neuronal survival that is induced by learning. Fifteen male Long-Evans rats were injected with bromodeoxyuridine (a marker for newborn cells; BrdU), implanted with hippocampal injection cannulae, and trained on a hippocampal-dependent odor discrimination learning task while being infused with either rimonabant, which effectively blocks the endocannabinoid system, vehicle (DMSO), or saline control. After the rats were sacrificed, brains were removed and newborn cells were visualized using immunohistochemical labeling of BrdU. Our behavioral results show that rimonabant rats tend to learn slower than saline control rats but no slower than the DMSO vehicle controls. This may imply that our vehicle impairs learning such that any effect of the CB1 antagonist cannot be distinguished. Though there were not enough subjects for formal statistical tests, preliminary histology data shows that vehicle, rimonabant, and saline rats have the most to least new cells numerically. It turns out that DMSO can cause neural damage and therefore may have led to gliosis and resulted in inflated cell counts. Future studies should continue to explore the questions of this study using a different vehicle, a larger sample size, and fluorescent double-labelling for neurons

Cocaine-induced structural plasticity in frontal cortex correlates with conditioned place preference.

Contextual cues associated with previous drug exposure can trigger drug craving and seeking, and form a substantial obstacle in substance use recovery. Using in vivo imaging in mice, we found that cocaine administration induced a rapid increase in the formation and accumulation of new dendritic spines, and that measures of new persistent spine gain correlated with cocaine conditioned place preference. Our data suggest that new persistent spine formation in the frontal cortex may be involved in stimulant-related learning driving appetitive behavior

Serotonergic modulation of fast-spiking interneurons in medial prefrontal cortex

The prefrontal cortex (PFC) functions to integrate information from the internal and external world in order to flexibly guide behavior. As the most recently evolved brain region, the PFC is implicated in a range of psychiatric disorders such as depression, anxiety, and schizophrenia. The circuitry within the PFC consists of a diversity of excitatory and inhibitory neurons and each neuronal subtype represents a unique locus for action by neuromodulators, such as dopamine and serotonin. The serotonergic system is heavily implicated in mood and emotion and is the target of many modern psychiatric drugs. Despite this, we have a limited understanding of the actions of serotonin on the diverse cell types in the PFC. In this dissertation, I describe the actions of serotonin (5HT) on interneurons and excitatory inputs arriving from discrete brain regions and suggest how this may relate to behavior and disease. I find that 5HT increases the excitability of fast-spiking interneurons but not somatostatin-expressing interneurons by reducing conductance through potassium channels, leading to enhanced summation of gamma frequency inputs. Furthermore, this causes an increase in gamma-frequency inhibitory events in downstream pyramidal cells, a finding which may contribute to my observation that serotonergic signaling reduces low frequency oscillatory power without changing in gamma power in vivo. I also describe how serotonin may act at multiple loci within the prefrontal circuit to reduce anxiety behavior. By both presynaptically suppressing ventral hippocampal inputs and increasing inhibition, 5HT may reduce theta oscillations and attenuate anxiety behavior. These findings may have wide implications for our understanding of psychiatric disorders

Serotonin 1B Receptors Regulate Prefrontal Function by Gating Callosal and Hippocampal Inputs

Both medial prefrontal cortex (mPFC) and serotonin play key roles in anxiety; however, specific mechanisms through which serotonin might act on the mPFC to modulate anxiety-related behavior remain unknown. Here, we use a combination of optogenetics and synaptic physiology to show that serotonin acts presynaptically via 5-HT1B receptors to selectively suppress inputs from the contralateral mPFC and ventral hippocampus (vHPC), while sparing those from mediodorsal thalamus. To elucidate how these actions could potentially regulate prefrontal circuit function, we infused a 5-HT1B agonist into the mPFC of freely behaving mice. Consistent with previous studies that have optogenetically inhibited vHPC-mPFC projections, activating prefrontal 5-HT1B receptors suppressed theta-frequency mPFC activity (4-12 Hz), and reduced avoidance of anxiogenic regions in the elevated plus maze. These findings suggest a potential mechanism, linking specific receptors, synapses, patterns of circuit activity, and behavior, through which serotonin may regulate prefrontal circuit function, including anxiety-related behaviors

A Visible-Light-Sensitive Caged Serotonin

Serotonin, or 5-hydroxytryptamine (5HT), is an important neurotransmitter in the nervous system of both vertebrates and invertebrates. Deficits in 5HT signaling are responsible for many disabling psychiatric conditions, and its molecular machinery is the target of many pharmaceuticals. We present a new 5HT phototrigger, the compound [Ru(bpy)2(PMe3)(5HT)]2+, where PMe3 is trimethylphosphine. As with other ruthenium-bipyridyl based caged compounds, [Ru(bpy)2(PMe3)(5HT)]2+ presents activity in the visible region of the spectrum. We characterize and discuss the photochemical properties of the caged compound, and demonstrate its use by modulating the excitability of mouse prefrontal principal neurons.Fil: Cabrera, Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Inorgánica, Analítica y Química Física; Argentina. Universidad de Buenos Aires. Ciclo Básico Común; ArgentinaFil: Filevich, Oscar. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: García Acosta, Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Inorgánica, Analítica y Química Física; ArgentinaFil: Athilingam, Jegath. UCSF Weill Institute for Neuroscience; Estados Unidos. University of California; Estados UnidosFil: Bender, Kevin J.. UCSF Weill Institute for Neuroscience; Estados Unidos. University of California; Estados UnidosFil: Poskanzer, Kira E.. UCSF Weill Institute for Neuroscience; Estados Unidos. University of California; Estados UnidosFil: Etchenique, Roberto Argentino. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Inorgánica, Analítica y Química Física; Argentin

Serotonin enhances excitability and gamma frequency temporal integration in mouse prefrontal fast-spiking interneurons.

The medial prefrontal cortex plays a key role in higher order cognitive functions like decision making and social cognition. These complex behaviors emerge from the coordinated firing of prefrontal neurons. Fast-spiking interneurons (FSIs) control the timing of excitatory neuron firing via somatic inhibition and generate gamma (30-100 Hz) oscillations. Therefore, factors that regulate how FSIs respond to gamma-frequency input could affect both prefrontal circuit activity and behavior. Here, we show that serotonin (5HT), which is known to regulate gamma power, acts via 5HT2A receptors to suppress an inward-rectifying potassium conductance in FSIs. This leads to depolarization, increased input resistance, enhanced spiking, and slowed decay of excitatory post-synaptic potentials (EPSPs). Notably, we found that slowed EPSP decay preferentially enhanced temporal summation and firing elicited by gamma frequency inputs. These findings show how changes in passive membrane properties can affect not only neuronal excitability but also the temporal filtering of synaptic inputs

A Visible-Light-Sensitive Caged Serotonin.

Serotonin, or 5-hydroxytryptamine (5HT), is an important neurotransmitter in the nervous system of both vertebrates and invertebrates. Deficits in 5HT signaling are responsible for many disabling psychiatric conditions, and its molecular machinery is the target of many pharmaceuticals. We present a new 5HT phototrigger, the compound [Ru(bpy)2(PMe3)(5HT)]2+, where PMe3 is trimethylphosphine. As with other ruthenium-bipyridyl based caged compounds, [Ru(bpy)2(PMe3)(5HT)]2+ presents activity in the visible region of the spectrum. We characterize and discuss the photochemical properties of the caged compound, and demonstrate its use by modulating the excitability of mouse prefrontal principal neurons

A Visible-Light-Sensitive Caged Serotonin.

Serotonin, or 5-hydroxytryptamine (5HT), is an important neurotransmitter in the nervous system of both vertebrates and invertebrates. Deficits in 5HT signaling are responsible for many disabling psychiatric conditions, and its molecular machinery is the target of many pharmaceuticals. We present a new 5HT phototrigger, the compound [Ru(bpy)2(PMe3)(5HT)]2+, where PMe3 is trimethylphosphine. As with other ruthenium-bipyridyl based caged compounds, [Ru(bpy)2(PMe3)(5HT)]2+ presents activity in the visible region of the spectrum. We characterize and discuss the photochemical properties of the caged compound, and demonstrate its use by modulating the excitability of mouse prefrontal principal neurons

Blunted responses to reward in remitted post-traumatic stress disorder

Background: Recent evidence suggests blunted responses to rewarding stimuli in patients with post-traumatic stress disorder (PTSD). However, it is not clear whether these alterations in reward processing normalize in remitted PTSD patients. Methods: We tested behavioral and physiological responses to monetary reward in a spatial memory task in 13 accident survivors with remitted PTSD, 14 accident survivors who never had PTSD, and 16 nontrauma-exposed subjects. All accident survivors were recruited from two samples of severely physically injured patients, who had participated in previous prospective studies on the incidence of PTSD after accidental injury approximately 10 years ago. Reaction time, accuracy, skin conductance responses, and self-reported mood were assessed during the task. Results: Accident survivors who never had PTSD and nontrauma exposed controls reported significantly higher positive mood in the reinforced versus nonreinforced condition (P < 0.045 and P < 0.001, respectively), while there was no effect of reinforcement in remitted PTSD subjects. Conclusions: Our findings suggest an alteration of the reward system in remitted PTSD. Further research is needed to investigate whether altered reward processing is a residual characteristic in PTSD after remission of symptoms or, alternatively, a preexisting risk factor for the development of PTSD after a traumatic event