Aberrations in brain serotonin (5-HT) neurotransmission have been implicated in psychiatric disorders including anxiety, depression and deficits in learning and memory. Many of these disorders are treated with drugs which promote the availability of 5-HT in the synapse. Selective serotonin uptake inhibitors (SSRIs) are known to stimulate the production of new neurons in the hippocampus (HPC) by increasing synaptic concentration of serotonin (5-HT). However, it is not clear which of the 5-HT receptors are involved in behavioral improvements and enhanced neurogenesis. The current study aimed to investigate the effects of 5HT2A agonists psilocybin and 251-NBMeO and the 5HT2A/C antagonist ketanserin on neurogenesis and hippocampal-dependent learning. Agonists and an antagonist to the 5-HT2A receptor produced alterations in hippocampal neurogenesis and trace fear conditioning. Future studies should examine the temporal effects of acute and chronic psilocybin administration on hippocampal-dependent learning and neurogenesis.

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The hippocampus appears to carry out spatial memory processing and navigation. As one of the inputs to the hippocampus originates in the perirhinal cortex and the spatial behaviour is affected by lesion of the perirhinal cortex, this structure may be critical for the functioning of hippocampal place cells. To investigate this hypothesis, the firing properties of hippocampal place cells were compared between control rats and rats with perirhinal cortex lesions. Rats were randomly assigned to control and lesion groups. Animals from both groups received recording electrode implantation and the lesion group rats received bilateral perirhinal cortex lesions. In experiment 1, the control and lesioned rats moved freely in an open field. In experiment 2, the control and lesion rats ran for reward in a linear track with either horizontal or vertical grating pattern stimulation along both sidewalls. These two experiments examined the spatial firing and movement-related firing properties of the control and lesion groups; and the theta-related firing properties of the two groups. In addition, experiment 2 investigated the influence of optic flow on these properties between the two groups. In experiment 3, the control and lesion rats were passively moved in the linear track with either a horizontal or vertical grating pattern on both sidewalls. This experiment examined the spatial firing and movement-related firing properties and also investigated the influences of optic flow, motor efferent and proprioceptive information on the firing properties of the control and lesion groups� place cells. The perirhinal cortex lesion affected the spatial firing properties of hippocampal place cells. The place field size in the lesion group was significantly reduced compared to the control group in both open field and linear track experiments. The lesion also altered the movement-related firing properties. The positive relationship between the animal�s movement speed and place cell�s firing rate was disrupted by the perirhinal cortex lesion whether the animals freely ran in the open field or in the linear track. In the open field study, the perirhinal cortex lesion altered the theta-related firing pattern, and the lesion disrupted phase precession in the linear track experiment. Phase precession is that when a rat passes through the place field, the firing of the cell advances progressively and systematically across the phase of the theta cycle from a late to an early phase of the cycle. The lesion also induced poorer theta "quality" of the EEG recorded at the hippocampal fissure. Optic flow affected the spatial firing of hippocampal place cells. The place field size was smaller in both the control and lesion group when the animals received vertical grating pattern stimulation compared to the horizontal grating condition. Change in the levels of optic flow stimulation did not, however, influence the relationship between the animal�s movement speed and place cell�s firing rate in the control group. When the animals were passively moved in a linear track, many of the place cells of both the groups stopped firing. The remaining cells from the control and lesion groups still displayed a place field. The cells in the control group lost the positive relationship between the animal�s movement speed and place cell�s firing rate. The perirhinal cortex lesion affected the spatial, movement- related and theta-related firing properties of hippocampal place cells. Change of optic flow had a subtle effect on the movement-related firing properties of the place cells. The PrhC lesion therefore disrupted motor efferent and proprioceptive input to the HPC rather than visual sensory information. Motor efferent / proprioceptive or vibrissae information may be conveyed from related cortex to the perirhinal cortex. This information may then project from the perirhinal cortex to the hippocampus directly or indirectly via the entorhinal cortex. Future studies could investigate the relationship between whisker stimulation and hippocampal place cell firing properties and further examine the possible role of motor efferent / proprioceptive signals in the firing of these cells.

Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) act as second messengers in intracellular signaling cascades to influence neuronal responses. Hippocampal cAMP signaling is thought to underlie the pathophysiology of major depressive disorder (MDD) and antidepressant action; however, little is known about the possible role of cGMP signaling. Furthermore, circadian rhythm disturbances can occur as part of the clinical symptoms of MDD and resolve with antidepressant therapy. The pineal gland is relevant to circadian rhythms as it secretes the hormone melatonin following activation of cAMP signaling and the rate-limiting enzyme for its synthesis, arylalkylamine N-acetyltransferase (AA-NAT). Little is known about the contribution of the phosphodiesterase (PDE) system to antidepressant-induced alterations in pineal cAMP signaling and melatonin synthesis. There is a need to clarify the trajectory of cAMP and cGMP concentrations, their synthesis by cyclases, and degradation by PDEs to understand the role of cyclic mononucleotide signaling in the effect of chronic antidepressant therapy. Using quantitative real-time PCR and enzyme immunoassay, we systematically studied elements of intracellular signaling in the hippocampus of rats chronically treated with imipramine, fluoxetine, and amitriptyline and in the pineal gland of rats treated chronically with fluoxetine. In the hippocampus, we found chronic imipramine downregulated cAMP signaling with decreased cAMP, increased PDEs and decreased adenylate cyclase mRNA. In contrast, repeated fluoxetine and amitriptyline increased hippocampal cGMP signaling, with increased cGMP and decreased PDE mRNA. We conclude that in contrast to the assumption of antidepressant-mediated increases in cAMP levels, increased hippocampal cGMP signaling might underlie the efficacy of chronic antidepressant treatment. A follow up study using cultured embryonic rat hippocampal cells in vitro treated with the PDE type 5 inhibitor, sildenafil, demonstrated increased cAMP content following acute and chronic treatment, indicating either crosstalk between cAMP and cGMP pathways or a non-specific inhibitory effect of sildenafil on other PDEs. In the pineal gland, we found elevated melatonin synthesis with increased pineal AA-NAT mRNA and daytime plasma melatonin and downregulated cAMP signaling with increased PDE and unchanged AC pineal mRNA, and decreased pineal cAMP. We conclude that chronic fluoxetine increases daytime plasma melatonin and pineal AA-NAT mRNA despite downregulated pineal cAMP signaling.

Fragile X syndrome (FXS) is caused by the lack of fragile X mental retardation protein (FMRP). The animal model of FXS, Fmr1 knockout (KO) mice, shows impairment in hippocampus-dependent learning and memory. However, results for long-term potentiation (LTP), remain inconclusive in the hippocampus of Fmr1 KO mice. Here, we demonstrate that FMRP is required for glycine-induced LTP (Gly-LTP) in the CA1 of hippocampus. The Gly-LTP requires activation of postsynaptic NMDA receptors and metabotropic glutamateric receptors, as well as the subsequent activation of extracellular signal-regulated kinase (ERK) 1/2. However, paired-pulse facilitation was not affected by glycine treatment. Our study provide evidences that FMRP participates in Gly-LTP by regulating the phosphorylation of ERK1/2, and that improper regulation of these signaling pathways may contribute to the learning and memory deficits observed in FXS.

Transforming growth factor-beta 1 (TGF-β1) is a multifunctional cytokine that orchestrates key events of development, disease and repair in the central nervous system (CNS). To investigate the effects of chronically producing TGF-β1 on synaptic structure and synaptic transmission, I performed immunohistochemistry and immunoblot of brain tissues from transgenic mice (TGF-β1 mice) that over-express active form of TGF-β1 from astrocytes in the CNS. Immunohistochemical assays showed that synaptophysin increased in the CA3 subfield whereas calbindin-D28K decreased in the mossy fibres. Immunoblot analysis revealed that several α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunit proteins were up-regulated in the hippocampus of TGF-β1 mice. To examine the direct effect of TGF-β1 alone on glutamatergic synaptic activity, cultured hippocampal neurons were treated with or without TGF-β1. Electrophysiological recordings displayed that TGF-β1 significantly increased the amplitude of glutamate-evoked current (p<0.05). Taken together, these data suggest that TGF-β1 modulates hippocampal glutamatergic synaptic protein expression and regulates synaptic transmission.

We conducted experiments to understand the role of Ventral Hippocampus (vHPC) projections to the Nucleus Accumbens (NAc) in exploratory locomotion, and to determine if the reduced vHPC parvalbumin neuron activity can result in behaviors associated with schizophrenia. Through the use of optogenetics, we activated vHPC neurons and vHPC terminals in the NAc. Both manipulations significantly increased locomotor activity in the open field. Selective inhibition of vHPC terminals in the NAc during a test for novel environment exploration significantly reduced preference for novel environments over familiar environments. DREADD-mediated inhibition of activation of vHPC parvalbumin neuron activity did not significantly alter amphetamine-induced locomotion. Overall, these experiments provide support for the role of the vHPC-NAc pathway in mediating exploratory behavior in novel environments, but it remains inconclusive whether dysregulated vHPC activity due to the loss of parvalbumin neurons leads to behaviors associated with schizophrenia.

Transforming growth factor-beta 1 (TGF-β1) is a multifunctional cytokine that orchestrates key events of development, disease and repair in the central nervous system (CNS). To investigate the effects of chronically producing TGF-β1 on synaptic structure and synaptic transmission, I performed immunohistochemistry and immunoblot of brain tissues from transgenic mice (TGF-β1 mice) that over-express active form of TGF-β1 from astrocytes in the CNS. Immunohistochemical assays showed that synaptophysin increased in the CA3 subfield whereas calbindin-D28K decreased in the mossy fibres. Immunoblot analysis revealed that several α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunit proteins were up-regulated in the hippocampus of TGF-β1 mice. To examine the direct effect of TGF-β1 alone on glutamatergic synaptic activity, cultured hippocampal neurons were treated with or without TGF-β1. Electrophysiological recordings displayed that TGF-β1 significantly increased the amplitude of glutamate-evoked current (p<0.05). Taken together, these data suggest that TGF-β1 modulates hippocampal glutamatergic synaptic protein expression and regulates synaptic transmission.

Kindling involves the progressive development of epileptiform activity that culminates in generalized seizures in response to repeated electrical stimulation of the brain. Kindling induces widespread changes in synaptic sensitivity and neuronal reactivity. These neuroplastic changes are evident in altered memory and behavior. This research was designed to further our understanding of kindling-induced deficits in spatial cognition. Two questions were examined: 1)does entorhinal cortex kindling disrupt spatial cognition; and 2)can bilateral bifocal kindling, of two brain regions known to participate in spatial cognition, produce larger cognitive deficits than unifocal kindling? This research attempted to confirm the spatial cognitive effects produced by unifocal dorsal hippocampal (dHPC) kindling, as a positive control. In contrast, the spatial cognitive effects produce by unifocal entorhinal cortex (EC) and bifocal kindling (i.e., EC kindling with subsequent contralateral dHPC kindling) are unknown and were examined here. Rats were subjected to unifocal EC kindling, unifocal dHPC kindling, or bifocal kindling. Rats exhibited fully generalized seizures prior to Morris water maze training from days 2 to 31. Visible platform trials were used to examine escape motivation and gross motor coordination, and all groups performed adequately. Consistent with previous research, dHPC kindling disrupted performance during acquisition trials; however, EC and bifocal kindling failed to disrupt acquisition. During retention trials, the bifocal kindling group displayed a disruption in performance; however, dHPC and lateral EC kindling failed to affect retention. The bifocal kindled group failed to display larger deficits than the unifocal kindled groups. These data suggest that the number of kindling stimulations given to a particular site may play a critical role in site-dependent disruption of memory.