Jorge H. Medina

The fate of memories depends mainly on two opposing forces: the mechanisms required for the storage and maintenance of memory and the mechanisms underlying forgetting, being the latter much less understood. Here, we show the effect of inhibiting the small Rho GTPase Rac1 on the fate of inhibitory avoidance memory in male rats. The immediate post-training micro-infusion of the specific Rac1 inhibitor NSC23766 (150 ng/0.5 µl/ side) into the ventral tegmental area (VTA) enhanced long-term memory at 1, 7, and 14 days after a single training. Additionally, an opposed effect occurred when the inhibitor was infused at 12 h after training while no effect was observed immediately after testing animals at 1 day. Control experiments ruled out the possibility that post-training memory enhancement was due to facilitation of memory formation since no effect was found when animals were tested at 1 h after acquisition and no memory enhancement was observed after the formation of a weak memory. Immediate post-training micro-infusion of Rac1 inhibitor into the dorsal hippocampus, or the amygdala did not affect memory. Our findings support the idea of a Rac1-dependent time-specific active forgetting mechanism in the VTA controlling the strength of a long-term aversive memory.

The fate of memories depends mainly on two opposing forces: the mechanisms required for the storage and maintenance of memory and the mechanisms underlying forgetting, being the latter much less understood. Here, we show the effect of inhibiting the small Rho GTPase Rac1 on the fate of inhibitory avoidance memory in male rats. The immediate post-training micro-infusion of the specific Rac1 inhibitor NSC23766 (150 ng/0.5 µl/ side) into the ventral tegmental area (VTA) enhanced long-term memory at 1, 7, and 14 days after a single training. Additionally, an opposed effect occurred when the inhibitor was infused at 12 h after training while no effect was observed immediately after testing animals at 1 d. Control experiments ruled out the possibility that post-training memory enhancement was due to facilitation of memory formation since no effect was found when animals were tested at 1 h after acquisition and no memory enhancement was observed after the formation of a weak memory. Immediate post-training micro-infusion of Rac1 inhibitor into the dorsal hippocampus, or the amygdala did not affect memory. Our findings support the idea of a Rac1-dependent time-specific active forgetting mechanism in the VTA controlling the strength of a long-term aversive memory.

Recently, it was reported that mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity during memory retrieval is required for normal expression of aversive and non-aversive long-term memories. Here we used inhibitory-avoidance task to evaluate the potential mechanisms by which mTORC1 signaling pathway participates in memory retrieval. First, we studied the role of GluA-subunit trafficking during memory recall and its relationship with mTORC1 pathway. We found that pretest intrahippocampal infusion of GluR23ɣ, a peptide that selectively blocks GluA2-containing AMPA receptor (AMPAR) endocytosis, prevented the amnesia induced by the inhibition of mTORC1 during retrieval. Additionally, we found that GluA1 levels decreased and GluA2 levels increased at the hippocampal postsynaptic density subcellular fraction of rapamycin-infused animals during memory retrieval. GluA2 levels remained intact while GluA1 decreased at the synaptic plasma membrane fraction. Then, we evaluated the requirement of AMPAR subunit expression during memory retrieval. Intrahippocampal infusion of GluA1 or GluA2 antisense oligonucleotides (ASO) 3 h before testing impaired memory retention. The memory impairment induced by GluA2 ASO before retrieval was reverted by GluA23ɣ infusion 1 h before testing. However, AMPAR endocytosis blockade was not sufficient to compensate GluA1 synthesis inhibition. Our work indicates that de novo GluA1 and GluA2 AMPAR subunit expression is required for memory retrieval with potential different roles for each subunit and suggests that mTORC1 might regulate AMPAR trafficking during retrieval. Our present results highlight the role of mTORC1 as a key determinant of memory retrieval that impacts the recruitment of different AMPAR subunits.

Fear is an extreme form of aversion that, if inappropriately generalized, initiates pathological conditions such as panic or anxiety. Fear conditioning (FC) is the best understood model of fear learning. During FC two independent associations link the cue and the training context to fear expression. The lateral habenula (LHb) is a general encoder of aversion. However, its role in fear learning has not been intensively studied. Here we studied the role of the LHb in FC using optogenetics and pharmacological tools in rats. Disrupting the neuronal activity of the LHb during training abolishes the expression of fear to isolated presentation of the training context or the cue, yet the recall of both associations when the cue is played in the training context reveals a conserved memory. Our results demonstrate that the LHb is required for the formation of independently expressible contextual and cued memories, a previously uncharacterized role in FC.

Dopamine (DA) neurons in the ventral tegmental area (VTA) are well-known components of the brain involved in reward-related behaviors and participate in the generation of new memories. Much attention has been focused to understand how DA neurons integrate a diversity of afferent signals with local excitatory and inhibitory influences regulated by somatodendritic release of dopamine. However, the mechanisms that actively forget rewarding information are still terra incognita. Using rodents in the conditioned place preference (CPP) behavioral task, we show that during acquisition D1-type DA receptors (D1R) in the VTA are crucial components of a neural circuit involving the hippocampus that induces active forgetting of cocaine-associated long-term memory, while VTA and nucleus accumbens (NAc) D1R are required for its formation. Inhibition of VTA D1R results in increased activation of VTA ERK1/2 and in prolonging memory storage of cocaine-place association in an ERK-dependent manner. Moreover, intra-VTA infusion of a specific D1 agonist induces forgetting of cocaine-associated consolidated memory. In contrast, D1R in the NAc shell, medial prefrontal cortex, or amygdala appear not to participate in the maintenance of cocaine-associated memory. Our present results suggest that at the moment of learning D1R-mediated neurotransmission in the VTA actively participates in at least two processes affecting the fate of appetitive memory: its consolidation involving NAc shell DA neurotransmission and its forgetting via DA activation of the hippocampus.

Extracellular regulated kinase 1/2 (ERK1/2) has been strongly implicated in several cellular processes. In the brain ERK1/2 activity has been primarily involved in long-term memory (LTM) formation and expression. Here, we review earlier evidence and describe recent developments of ERK1/2 signaling in memory processing focusing the attention on the role of ERK1/2 in memory retrieval and reconsolidation, and in the maintenance of the memory trace including mechanisms involving the protection of labile memories. In addition, relearning requires ERK1/2 activity in selected brain regions. Its involvement in distinct memory stages points at ERK1/2 as a core element in memory processing and as one likely target to treat memory impairments associated with neurological disorders.

Understanding how stored information emerges is a main question in the neurobiology of memory that is now increasingly gaining attention. However, molecular events underlying this memory stage, including involvement of protein synthesis, are not well defined. Mammalian target of rapamycin complex 1 (mTORC1), a central regulator of protein synthesis, has been implicated in synaptic plasticity and is required for memory formation. Using inhibitory avoidance (IA), we evaluated the role of mTORC1 in memory retrieval. Infusion of a selective mTORC1 inhibitor, rapamycin, into the dorsal hippocampus 15 or 40 min but not 3 h before testing at 24 h reversibly disrupted memory expression even in animals that had already expressed IA memory. Emetine, a general protein synthesis inhibitor, provoked a similar impairment. mTORC1 inhibition did not interfere with short-term memory retrieval. When infused before test at 7 or 14 but not at 28 days after training, rapamycin impaired memory expression. mTORC1 blockade in retrosplenial cortex, another structure required for IA memory, also impaired memory retention. In addition, pretest intrahippocampal rapamycin infusion impaired object location memory retrieval. Our results support the idea that ongoing protein synthesis mediated by activation of mTORC1 pathway is necessary for long but not for short term memory.

Quercus macdougallii Martínez es una especie endémica y amenazada de la Sierra Juárez, Oaxaca, México, que requiere de aplicar estrategias de preservación in situ de sus poblaciones para promover su permanencia a largo plazo. Para lograrlo, es necesario conocer los mecanismos de reproducción sexual de esta especie. Este trabajo, analiza factores que afectan el establecimiento y el crecimiento de plántulas de Q. macdougallii, con la finalidad de dar recomendaciones para su preservación in situ. El estudio se realizó de 2009 a 2010 y consistió en cuantificar la producción de bellotas, estimar porcentajes de depredación y parasitismo, estimar germinación de bellotas y evaluar el crecimiento y la supervivencia de plántulas. Los primeros dos objetivos se realizaron en condiciones de campo y laboratorio, mientras que el tercer objetivo solo fue analizado en condiciones de laboratorio. Paralelamente, se realizó un experimento para estimar el éxito de un plan de reforestación realizado tanto en condiciones de disturbio, como en condiciones sin distubio. Los resultados obtenidos sugieren que la especie estudiada presenta una producción promedio de 1735 ± 832 bellotas, una baja depredación por consumo (< 7%) y un parasitismo de 8.7%. La germinación y el crecimiento en campo y en laboratorio fueron mayores en bellotas grandes (> 1.701 g) que en medianas (1.045 g - 1.70 g) y pequeñas (0.350 g - 1.044 g), con un porcentaje de germinación promedio de 50%. La supervivencia de plántulas fue de 10% en sitios con disturbio y de 75% en condiciones sin disturbios. Se sugiere recolectar bellotas grandes para realizar programas de reforestación; para ello, es recomendable poner a germinar las bellotas en el laboratorio, dejarlas crecer durante seis meses y trasplantarlas al inicio de la época de lluvia y bajo el dosel de árboles madre.

The neurobiology of memory formation attracts much attention in the last five decades. Conversely, the rules that govern and the mechanisms underlying forgetting are less understood. In addition to retroactive interference, retrieval-induced forgetting and passive decay of time, it has been recently demonstrated that the nervous system has a diversity of active and inherent processes involved in forgetting. In Drosophila, some operate mainly at an early stage of memory formation and involves dopamine (DA) neurons, specific postsynaptic DA receptor subtypes, Rac1 activation and induces rapid active forgetting. In mammals, others regulate forgetting and persistence of seemingly consolidated memories and implicate the activity of DA receptor subtypes and AMPA receptors in the hippocampus (HP) and related structures to activate parallel signaling pathways controlling active time-dependent forgetting. Most of them may involve plastic changes in synaptic and extrasynaptic receptors including specific removal of GluA2 AMPA receptors. Forgetting at longer timescales might also include changes in adult neurogenesis in the dentate gyrus (DG) of the HP. Therefore, based on relevance or value considerations neuronal circuits may regulate in a time-dependent manner what is formed, stored, and maintained and what is forgotten.

It is well established that neurons of the mammalian medial prefrontal cortex (mPFC) modulate different behavioral outputs, including several memory types. This behavioral modulation is, at least in part, under the control of the D1-like dopamine receptor (D1/5R) which comprises D1 and D5-specific subtypes (D1R and D5R, respectively). Here, combining a set of behavioral assays with pharmacology we determined whether the activation of D1/5R in the mPFC during almost neutral or weak negative-valence experiences induces aversive behaviors. The intra mPFC bilateral infusion of the D1/5R agonist SKF 38393 (6.25 µg/side) immediately after exposing rats to the white compartment of a place conditioning apparatus promotes a incubated-like aversive memory when tested 7 days thereafter, but it was not seen 24 hours after conditioning. No signs of fear or changes in the anxiety state were observed after the exposure to the white compartment. This aversive response is observed only when the experience paired with the mPFC D1/5R activation has a context component involved. By using specific agonists for D1R or D5R subtypes we suggest that D5R mediate the induction of the aversive behavior. No aversive effects were observed when the D1/5R agonist was infused into the dorsal hippocampus (HP), the nucleus accumbens (NAcc) or the basolateral amygdala (BLA) of rats exposed to the white compartment. Taken together, our present findings endorse the idea that activation of mPFC D1/5R is sufficient to induce incubated-like aversive memories after exposing rats to an apparent neutral or weak negative-valence environment and that mPFC might be considered a key brain region involved in providing adaptive emotional behaviors in response to an ever-changing environment.