Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders

Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ 9 -tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca 2+ ) increase, etc.), on CBD behavioural effects.

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Is adult hippocampal neurogenesis really relevant for the treatment of psychiatric disorders?

Current Neuropharmacology ◽

10.2174/1570159x18666200818194948 ◽

2020 ◽

Vol 18 ◽

Author(s):

Marco Carli ◽

Stefano Aringhieri ◽

Shivakumar Kolachalam ◽

Biancamaria Longoni ◽

Giovanna Grenno ◽

...

Keyword(s):

Psychiatric Disorders ◽

Emotional Processing ◽

Imaging Techniques ◽

Hippocampal Neurogenesis ◽

Adult Brain ◽

Adult Hippocampal Neurogenesis ◽

Mood Stabilizers ◽

Post Traumatic Stress ◽

Newborn Neurons ◽

Hippocampal Circuitry

: Adult neurogenesis consists in the generation of newborn neurons from neural stem cells taking place in the adult brain. In mammals, this process is limited to very few areas of the brain, and one of these neurogenic niches is the subgranular layer of the dentate gyrus (DG) of the hippocampus. Adult newborn neurons are generated from quiescent neural progenitors (QNPs), which differentiate through different steps into mature granule cells (GCs), to be finally integrated into the existing hippocampal circuitry. In animal models, adult hippocampal neurogenesis (AHN) is relevant for pattern discrimination, cognitive flexibility, emotional processing and resilience to stressful situations. Imaging techniques allow to visualize newborn neurons within the hippocampus through all their stages of development and differentiation. In humans, the evidence of AHN is more challenging, and, based on recent findings, it persists through the adulthood, even if it declines with age. Whether this process has an important role in human brain function and how it integrates into the existing hippocampal circuitry is still a matter of exciting debate. Importantly, AHN deficiency has been proposed to be relevant in many psychiatric disorders, including mood disorders, anxiety, post-traumatic stress disorder and schizophrenia. This review aims to investigate how AHN is altered in different psychiatric conditions and how pharmacological treatments can rescue this process. In fact, many psychoactive drugs, such as antidepressants, mood stabilizers and atypical antipsychotics (AAPs), can boost AHN with different results. In addition, some non-pharmacological approaches are discussed as well.

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Enriched Environment Ameliorates Adult Hippocampal Neurogenesis Deficits in Tcf4 Haploinsufficient Mice

10.21203/rs.3.rs-44375/v1 ◽

2020 ◽

Author(s):

Katharina Braun ◽

Benjamin M. Häberle ◽

Marie-Theres Wittmann ◽

Dieter Chichung Lie

Keyword(s):

Transcription Factor ◽

Intellectual Disability ◽

Knockout Mice ◽

Negative Impact ◽

Brain Regions ◽

Nervous System Development ◽

Hippocampal Neurogenesis ◽

Enriched Environment ◽

Adult Hippocampal Neurogenesis ◽

Wide Range

Abstract Background: Transcription factor 4 (TCF4) has been linked to human neurodevelopmental disorders such as intellectual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated that TCF4 participates in the control of a wide range of neurodevelopmental processes in mammalian nervous system development including neural precursor proliferation, timing of differentiation, migration, dendritogenesis and synapse formation. TCF4 is highly expressed in the adult hippocampal dentate gyrus – one of the few brain regions where neural stem / progenitor cells generate new functional neurons throughout life.Results: We here investigated whether TCF4 haploinsufficiency, which in humans causes non-syndromic forms of intellectual disability and PTHS, affects adult hippocampal neurogenesis, a process that is essential for hippocampal plasticity in rodents and potentially in humans. Young adult Tcf4 heterozygote knockout mice showed a major reduction in the level of adult hippocampal neurogenesis, which was at least in part caused by lower stem/progenitor cell numbers and impaired maturation and survival of adult-generated neurons. Interestingly, housing in an enriched environment was sufficient to enhance maturation and survival of new neurons and to substantially augment neurogenesis levels in Tcf4 heterozygote knockout mice.Conclusion: Haploinsufficiency for the transcription factor TCF4 has been linked to non-syndromic intellectual disability and PTHS. The present findings raise the possibility that TCF4 haploinsufficiency may have a continuous negative impact on hippocampal function by impeding hippocampal neurogenesis and suggest that behavioural stimulation may be harnessed to ameliorate a subset of TCF4 haploinsufficiency associated neural deficits during adulthood.

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Differential inhibition onto developing and mature granule cells generates high-frequency filters with variable gain

eLife ◽

10.7554/elife.08764 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 15

Author(s):

María Belén Pardi ◽

Mora Belén Ogando ◽

Alejandro F Schinder ◽

Antonia Marin-Burgin

Keyword(s):

Granule Cells ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Information Encoding ◽

High Frequencies ◽

Wide Range ◽

Mature Neurons ◽

Different Populations ◽

Immature Cells ◽

Two Populations

Adult hippocampal neurogenesis provides the dentate gyrus with heterogeneous populations of granule cells (GC) originated at different times. The contribution of these cells to information encoding is under current investigation. Here, we show that incoming spike trains activate different populations of GC determined by the stimulation frequency and GC age. Immature GC respond to a wider range of stimulus frequencies, whereas mature GC are less responsive at high frequencies. This difference is dictated by feedforward inhibition, which restricts mature GC activation. Yet, the stronger inhibition of mature GC results in a higher temporal fidelity compared to that of immature GC. Thus, hippocampal inputs activate two populations of neurons with variable frequency filters: immature cells, with wide‐range responses, that are reliable transmitters of the incoming frequency, and mature neurons, with narrow frequency response, that are precise at informing the beginning of the stimulus, but with a sparse activity.

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Selective increases in inter-individual variability in response to environmental enrichment in female mice

eLife ◽

10.7554/elife.35690 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 12

Author(s):

Julia C Körholz ◽

Sara Zocher ◽

Anna N Grzyb ◽

Benjamin Morisse ◽

Alexandra Poetzsch ◽

...

Keyword(s):

Environmental Enrichment ◽

Specific Activity ◽

Individual Variability ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Multiple Parameters ◽

Wide Range ◽

Suitable Animal Model ◽

Brain And Behavior ◽

And Behavior

One manifestation of individualization is a progressively differential response of individuals to the non-shared components of the same environment. Individualization has practical implications in the clinical setting, where subtle differences between patients are often decisive for the success of an intervention, yet there has been no suitable animal model to study its underlying biological mechanisms. Here we show that enriched environment (ENR) can serve as a model of brain individualization. We kept 40 isogenic female C57BL/6JRj mice for 3 months in ENR and compared these mice to an equally sized group of standard-housed control animals, looking at the effects on a wide range of phenotypes in terms of both means and variances. Although ENR influenced multiple parameters and restructured correlation patterns between them, it only increased differences among individuals in traits related to brain and behavior (adult hippocampal neurogenesis, motor cortex thickness, open field and object exploration), in agreement with the hypothesis of a specific activity-dependent development of brain individuality.

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The Contribution of Adult Hippocampal Neurogenesis to the Progression of Psychiatric Disorders

Modern Trends in Pharmacopsychiatry - Neuroprogression in Psychiatric Disorders ◽

10.1159/000470812 ◽

2017 ◽

pp. 124-151 ◽

Cited By ~ 5

Author(s):

Rachel A. Kohman ◽

Justin S. Rhodes

Keyword(s):

Psychiatric Disorders ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis

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Functional Role of Adult Hippocampal Neurogenesis as a Therapeutic Strategy for Mental Disorders

Neural Plasticity ◽

10.1155/2012/854285 ◽

2012 ◽

Vol 2012 ◽

pp. 1-20 ◽

Cited By ~ 52

Author(s):

Heechul Jun ◽

Syed Mohammed Qasim Hussaini ◽

Michael J. Rigby ◽

Mi-Hyeon Jang

Keyword(s):

Mental Disorders ◽

Psychiatric Disorders ◽

Adult Neurogenesis ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Mammalian Brain ◽

Antidepressant Effect ◽

Highly Correlated ◽

Deep Brain

Adult neurogenesis, the process of generating new neurons from neural stem cells, plays significant roles in synaptic plasticity, memory, and mood regulation. In the mammalian brain, it continues to occur well into adulthood in discrete regions, namely, the hippocampus and olfactory bulb. During the past decade, significant progress has been made in understanding the mechanisms regulating adult hippocampal neurogenesis and its role in the etiology of mental disorders. In addition, adult hippocampal neurogenesis is highly correlated with the remission of the antidepressant effect. In this paper, we discuss three major psychiatric disorders, depression, schizophrenia, and drug addiction, in light of preclinical evidence used in establishing the neurobiological significance of adult neurogenesis. We interpret the significance of these results and pose questions that remain unanswered. Potential treatments which include electroconvulsive therapy, deep brain stimulation, chemical antidepressants, and exercise therapy are discussed. While consensus lacks on specific mechanisms, we highlight evidence which indicates that these treatments may function via an increase in neural progenitor proliferation and changes to the hippocampal circuitry. Establishing a significant role of adult neurogenesis in the pathogenicity of psychiatric disorders may hold the key to potential strategies toward effective treatment.

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Selective increases in inter-individual variability in response to environmental enrichment

10.1101/260455 ◽

2018 ◽

Cited By ~ 1

Author(s):

Julia Körholz ◽

Sara Zocher ◽

Anna N. Grzyb ◽

Benjamin Morisse ◽

Alexandra Poetzsch ◽

...

Keyword(s):

Environmental Enrichment ◽

Specific Activity ◽

Individual Variability ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Multiple Parameters ◽

Wide Range ◽

Suitable Animal Model ◽

Brain And Behavior ◽

And Behavior

AbstractOne manifestation of individualization is a progressively differential response of individuals to the non-shared components of the same environment. Individualization has practical implications in clinical setting, where subtle differences between patients are often decisive for the success of an intervention, yet there has been no suitable animal model to study its underlying biological mechanisms. Here we show that enriched environment (ENR) can serve as a model of brain individualization. We kept 40 isogenic mice for 3 months in ENR and compared the effects on a wide range of phenotypes on both mean and variance to an equally sized group of standard-housed control animals. While ENR influenced multiple parameters and restructured correlation patterns between them, it only increased differences among individuals in traits related to brain and behavior (adult hippocampal neurogenesis, motor cortex thickness, open field and object exploration, rotarod performance), in agreement with the hypothesis of a specific activity-dependent development of brain individuality.

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Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

10.21203/rs.3.rs-44375/v3 ◽

2020 ◽

Author(s):

Katharina Braun ◽

Benjamin M. Häberle ◽

Marie-Theres Wittmann ◽

Dieter Chichung Lie

Keyword(s):

Transcription Factor ◽

Intellectual Disability ◽

Knockout Mice ◽

Negative Impact ◽

Brain Regions ◽

Nervous System Development ◽

Hippocampal Neurogenesis ◽

Enriched Environment ◽

Adult Hippocampal Neurogenesis ◽

Wide Range

Abstract Background: Transcription factor 4 (TCF4) has been linked to human neurodevelopmental disorders such as intellectual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated that TCF4 participates in the control of a wide range of neurodevelopmental processes in mammalian nervous system development including neural precursor proliferation, timing of differentiation, migration, dendritogenesis and synapse formation. TCF4 is highly expressed in the adult hippocampal dentate gyrus – one of the few brain regions where neural stem / progenitor cells generate new functional neurons throughout life.Results: We here investigated whether TCF4 haploinsufficiency, which in humans causes non-syndromic forms of intellectual disability and PTHS, affects adult hippocampal neurogenesis, a process that is essential for hippocampal plasticity in rodents and potentially in humans. Young adult Tcf4 heterozygote knockout mice showed a major reduction in the level of adult hippocampal neurogenesis, which was at least in part caused by lower stem/progenitor cell numbers and impaired maturation and survival of adult-generated neurons. Interestingly, housing in an enriched environment was sufficient to enhance maturation and survival of new neurons and to substantially augment neurogenesis levels in Tcf4 heterozygote knockout mice.Conclusion:The present findings indicate that haploinsufficiency for the intellectual disability- and PTHS-linked transcription factor TCF4 not only affects embryonic neurodevelopment but impedes neurogenesis in the hippocampus of adult mice. These findings suggest that TCF4 haploinsufficiency may have a negative impact on hippocampal function throughout adulthood by impeding hippocampal neurogenesis.

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Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

10.21203/rs.3.rs-44375/v2 ◽

2020 ◽

Author(s):

Katharina Braun ◽

Benjamin M. Häberle ◽

Marie-Theres Wittmann ◽

Dieter Chichung Lie

Keyword(s):

Transcription Factor ◽

Intellectual Disability ◽

Knockout Mice ◽

Negative Impact ◽

Brain Regions ◽

Nervous System Development ◽

Hippocampal Neurogenesis ◽

Enriched Environment ◽

Adult Hippocampal Neurogenesis ◽

Wide Range

Abstract Background: Transcription factor 4 (TCF4) has been linked to human neurodevelopmental disorders such as intellectual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated that TCF4 participates in the control of a wide range of neurodevelopmental processes in mammalian nervous system development including neural precursor proliferation, timing of differentiation, migration, dendritogenesis and synapse formation. TCF4 is highly expressed in the adult hippocampal dentate gyrus – one of the few brain regions where neural stem / progenitor cells generate new functional neurons throughout life.Results: We here investigated whether TCF4 haploinsufficiency, which in humans causes non-syndromic forms of intellectual disability and PTHS, affects adult hippocampal neurogenesis, a process that is essential for hippocampal plasticity in rodents and potentially in humans. Young adult Tcf4 heterozygote knockout mice showed a major reduction in the level of adult hippocampal neurogenesis, which was at least in part caused by lower stem/progenitor cell numbers and impaired maturation and survival of adult-generated neurons. Interestingly, housing in an enriched environment was sufficient to enhance maturation and survival of new neurons and to substantially augment neurogenesis levels in Tcf4 heterozygote knockout mice.Conclusion: The present findings indicate that haploinsufficiency for the intellectual disability- and PTHS-linked transcription factor TCF4 not only affects embryonic neurodevelopment but impedes neurogenesis in the hippocampus of adult mice. These findings suggest that TCF4 haploinsufficiency may have a negative impact on hippocampal function throughout adulthood by impeding hippocampal neurogenesis.

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Surveillance, Phagocytosis, and Inflammation: How Never-Resting Microglia Influence Adult Hippocampal Neurogenesis

Neural Plasticity ◽

10.1155/2014/610343 ◽

2014 ◽

Vol 2014 ◽

pp. 1-15 ◽

Cited By ~ 119

Author(s):

Amanda Sierra ◽

Sol Beccari ◽

Irune Diaz-Aparicio ◽

Juan M. Encinas ◽

Samuel Comeau ◽

...

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Cells ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Trophic Factors ◽

Normal Brain ◽

Positive Contribution ◽

Brain Functions ◽

Wide Range ◽

Trauma Injury

Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory.

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